Effect of BNP-Guided Treatment of Chronic HF on Mortality
Effect of BNP-Guided Treatment of Chronic HF on Mortality
Aims Natriuretic peptide-guided (NP-guided) treatment of heart failure has been tested against standard clinically guided care in multiple studies, but findings have been limited by study size. We sought to perform an individual patient data meta-analysis to evaluate the effect of NP-guided treatment of heart failure on all-cause mortality.
Methods and results Eligible randomized clinical trials were identified from searches of Medline and EMBASE databases and the Cochrane Clinical Trials Register. The primary pre-specified outcome, all-cause mortality was tested using a Cox proportional hazards regression model that included study of origin, age (<75 or ≥75 years), and left ventricular ejection fraction (LVEF, ≤45 or >45%) as covariates. Secondary endpoints included heart failure or cardiovascular hospitalization. Of 11 eligible studies, 9 provided individual patient data and 2 aggregate data. For the primary endpoint individual data from 2000 patients were included, 994 randomized to clinically guided care and 1006 to NP-guided care. All-cause mortality was significantly reduced by NP-guided treatment [hazard ratio = 0.62 (0.45–0.86); P = 0.004] with no heterogeneity between studies or interaction with LVEF. The survival benefit from NP-guided therapy was seen in younger (<75 years) patients [0.62 (0.45–0.85); P = 0.004] but not older (≥75 years) patients [0.98 (0.75–1.27); P = 0.96]. Hospitalization due to heart failure [0.80 (0.67–0.94); P = 0.009] or cardiovascular disease [0.82 (0.67–0.99); P = 0.048] was significantly lower in NP-guided patients with no heterogeneity between studies and no interaction with age or LVEF.
Conclusion Natriuretic peptide-guided treatment of heart failure reduces all-cause mortality in patients aged <75 years and overall reduces heart failure and cardiovascular hospitalization.
How best to guide the complex pharmacotherapy of chronic heart failure is in dispute. Whereas some medications, namely angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor antagonists, certain beta-blockers (BB), and mineralocorticoid receptor antagonists (MRA) have been shown to improve survival in patients with chronic heart failure and a reduced left ventricular ejection fraction (LVEF), the optimal dosage of these agents in individuals is guided largely by subjective indices, namely the clinician's assessment of symptoms, bedside signs and tolerability. Consequently, evidence-based target doses of these proven medications are rarely achieved outside the clinical trial setting, even in eligible patients. Despite lack of trial evidence for longevity benefit, loop and/or thiazide-like diuretics are seen as central to the treatment of almost all patients with chronic heart failure. Here again, optimal or target doses are dictated largely by clinician interpretation of the patient's symptoms and signs. It would obviously be useful if pharmacotherapy could be directed not only by subjective bedside indices but also by an objective index of circulatory status. In this regard, it has been proposed that circulating levels of the B-type cardiac natriuretic peptides (BNP and NT-proBNP), which are released from the heart in proportion to stretch of the cardiac chambers, might provide such an objective guide. This proposition is reinforced first, by evidence that circulating levels of these peptides and change in their levels over time provide a robust prognostic index in chronic heart failure and second, each of the drug groups which demonstrably increase longevity, as well as loop diuretics, reduce their levels in the circulation.
Several studies have addressed the hypothesis, first proposed in the late 1990s, that pharmacotherapy guided by BNP or NT-proBNP levels (NP-guided treatment) would improve clinical outcomes. While some of these studies demonstrated a reduction in combined clinical events, no single study was adequately powered to test the effect of this strategy on all-cause mortality—the ultimate clinically relevant endpoint.
In viewing results from published studies, the European Society of Cardiology, the National Institute for Health and Clinical Excellence (NICE), the American College of Cardiology/American Heart Association, the National Academy of Clinical Biochemistry, and the National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand opined that the evidence is insufficient to support routine NP-guided treatment over conventional care.
Previous literature-based meta-analyses using aggregate data have suggested that NP-guided treatment may be associated with a 20–30% reduction in all-cause mortality. Such meta-analyses, however, can have important limitations relating to potential heterogeneity of patient characteristics and outcome definitions. In contrast, meta-analyses based on individual patient data allow more rigorous testing with the incorporation of standard outcome definitions and provide the opportunity to consider important patient characteristics that could influence outcomes or mitigate/moderate the effects of treatment interventions on outcomes. Accordingly, we performed an individual patient data meta-analysis, which includes data from studies published subsequent to two of the earlier aggregate data meta-analyses to test the hypothesis that compared with conventional clinically guided management, NP-guided therapy results in a reduction in all-cause mortality.
Abstract and Introduction
Abstract
Aims Natriuretic peptide-guided (NP-guided) treatment of heart failure has been tested against standard clinically guided care in multiple studies, but findings have been limited by study size. We sought to perform an individual patient data meta-analysis to evaluate the effect of NP-guided treatment of heart failure on all-cause mortality.
Methods and results Eligible randomized clinical trials were identified from searches of Medline and EMBASE databases and the Cochrane Clinical Trials Register. The primary pre-specified outcome, all-cause mortality was tested using a Cox proportional hazards regression model that included study of origin, age (<75 or ≥75 years), and left ventricular ejection fraction (LVEF, ≤45 or >45%) as covariates. Secondary endpoints included heart failure or cardiovascular hospitalization. Of 11 eligible studies, 9 provided individual patient data and 2 aggregate data. For the primary endpoint individual data from 2000 patients were included, 994 randomized to clinically guided care and 1006 to NP-guided care. All-cause mortality was significantly reduced by NP-guided treatment [hazard ratio = 0.62 (0.45–0.86); P = 0.004] with no heterogeneity between studies or interaction with LVEF. The survival benefit from NP-guided therapy was seen in younger (<75 years) patients [0.62 (0.45–0.85); P = 0.004] but not older (≥75 years) patients [0.98 (0.75–1.27); P = 0.96]. Hospitalization due to heart failure [0.80 (0.67–0.94); P = 0.009] or cardiovascular disease [0.82 (0.67–0.99); P = 0.048] was significantly lower in NP-guided patients with no heterogeneity between studies and no interaction with age or LVEF.
Conclusion Natriuretic peptide-guided treatment of heart failure reduces all-cause mortality in patients aged <75 years and overall reduces heart failure and cardiovascular hospitalization.
Introduction
How best to guide the complex pharmacotherapy of chronic heart failure is in dispute. Whereas some medications, namely angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor antagonists, certain beta-blockers (BB), and mineralocorticoid receptor antagonists (MRA) have been shown to improve survival in patients with chronic heart failure and a reduced left ventricular ejection fraction (LVEF), the optimal dosage of these agents in individuals is guided largely by subjective indices, namely the clinician's assessment of symptoms, bedside signs and tolerability. Consequently, evidence-based target doses of these proven medications are rarely achieved outside the clinical trial setting, even in eligible patients. Despite lack of trial evidence for longevity benefit, loop and/or thiazide-like diuretics are seen as central to the treatment of almost all patients with chronic heart failure. Here again, optimal or target doses are dictated largely by clinician interpretation of the patient's symptoms and signs. It would obviously be useful if pharmacotherapy could be directed not only by subjective bedside indices but also by an objective index of circulatory status. In this regard, it has been proposed that circulating levels of the B-type cardiac natriuretic peptides (BNP and NT-proBNP), which are released from the heart in proportion to stretch of the cardiac chambers, might provide such an objective guide. This proposition is reinforced first, by evidence that circulating levels of these peptides and change in their levels over time provide a robust prognostic index in chronic heart failure and second, each of the drug groups which demonstrably increase longevity, as well as loop diuretics, reduce their levels in the circulation.
Several studies have addressed the hypothesis, first proposed in the late 1990s, that pharmacotherapy guided by BNP or NT-proBNP levels (NP-guided treatment) would improve clinical outcomes. While some of these studies demonstrated a reduction in combined clinical events, no single study was adequately powered to test the effect of this strategy on all-cause mortality—the ultimate clinically relevant endpoint.
In viewing results from published studies, the European Society of Cardiology, the National Institute for Health and Clinical Excellence (NICE), the American College of Cardiology/American Heart Association, the National Academy of Clinical Biochemistry, and the National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand opined that the evidence is insufficient to support routine NP-guided treatment over conventional care.
Previous literature-based meta-analyses using aggregate data have suggested that NP-guided treatment may be associated with a 20–30% reduction in all-cause mortality. Such meta-analyses, however, can have important limitations relating to potential heterogeneity of patient characteristics and outcome definitions. In contrast, meta-analyses based on individual patient data allow more rigorous testing with the incorporation of standard outcome definitions and provide the opportunity to consider important patient characteristics that could influence outcomes or mitigate/moderate the effects of treatment interventions on outcomes. Accordingly, we performed an individual patient data meta-analysis, which includes data from studies published subsequent to two of the earlier aggregate data meta-analyses to test the hypothesis that compared with conventional clinically guided management, NP-guided therapy results in a reduction in all-cause mortality.
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