EDITORIAL COMMENT
Are BNP Changes During Hospitalization for Heart Failure a Reliable Surrogate for Predicting the Effects of Therapies on Post-Discharge Mortality?*
Mihai Gheorghiade, MD ,* and
Peter S. Pang, MD
Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
Department of Emergency Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
* Reprint requests and correspondence: Dr. Mihai Gheorghiade, Northwestern University Feinberg School of Medicine, 676 N. St. Clair, Suite 600, Chicago, Illinois 60611 (Email: m-gheorghiade{at}northwestern.edu).
Key Words: B-type natriuretic peptide • acute decompensation of heart failure • levosimendan • dobutamine • prognosis
Since the discovery of B-type natriuretic peptide (BNP) as a cardiac hormone in 1991, it has been well studied as a diagnostic and prognostic marker in heart failure (HF). BNP has also been investigated for its role in cost-effectiveness, as a guide to therapy, as a therapy itself, as inclusion criteria for clinical research, and as an end point/surrogate marker in clinical trials (1–6). BNP is secreted primarily by cardiac myocytes in response to stretch, due to pressure or volume overload (7). BNP acts as a counter-regulatory hormone, counterbalancing the negative effects of the renin-angiotensin-aldosterone system and sympathetic nervous system (SNS) by promoting vasodilation, diuresis, and natriuresis (1,8). Although BNP-guided therapy has shown some promise (9), reductions in BNP alone, however, are not acceptable for regulatory approval of novel therapies and remain an area of debate (10).
In this issue of the Journal, Cohen-Solal et al. (11) report their findings from a retrospective analysis of the SURVIVE (Survival in Patients with Acute Heart Failure in Need of Intravenous Inotropic Support) trial, of patients who were randomized to levosimendan or dobutamine. In this highly select group of patients, the authors examined measured BNP at days 1, 3, and 5 and correlated changes over time with mortality. Patients with reductions in BNP >30% or an absolute reduction to <800 pg/ml over the first 5 days had better survival at 31 and 180 days. Changes in BNP were observed in the context of a short-term intervention during hospitalization with either levosimendan or dobutamine when added to standard therapy that included diuretics, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, aldosterone antagonists, and beta-blockers. The lower BNP levels in this study may reflect the hemodynamic changes that were seen with levosimendan in the LIDO (Levosimendan Infusion versus Dobutamine) trial (12).
The conclusions of this study should be interpreted with caution. Several well-validated prognostic variables, including blood urea nitrogen, serum sodium, heart rate, and age, were not included in the model. Although SBP at baseline is accounted for, there was no assessment of whether SBP at day 5 or changes in SBP would have been as or more predictive compared to changes in BNP. It is interesting that patients with higher mortality had a lower BNP at baseline. This contradicts available data, which suggest that prognosis is associated with higher BNP levels (5). However, it is possible that changes in BNP are more powerful predictors than baseline value.
The authors' conclusion is appealing: reduction of BNP levels over 5 days as part of an in-hospital treatment algorithm will facilitate optimization of therapy, resulting in better post-discharge outcomes. Although the authors clearly state that this requires confirmatory testing, such a hypothesis has important implications for clinical practice and clinical trials in acute heart failure syndromes (AHFS) because the number of patients hospitalized with HF continues to grow. AHFS is associated with a cost exceeding $17 billion per year with over 3 million hospital diagnoses each year and more expected as the population ages. Although most patients appear to improve during hospitalization with available therapies, their post-discharge rehospitalization and mortality rates within 60 days can be as high as 30% to 40% (13–15). Attempts to improve clinical outcomes with novel therapies have largely failed in terms of efficacy and/or safety (6,16–20). Given the difficulties in conducting large-scale mortality trials in AHFS, an accepted surrogate marker for outcomes, such as BNP, may provide objective proof of the efficacy of interventions during hospitalization to improve long-term outcomes.
However, prior data from the levosimendan clinical development program suggest a different conclusion from that suggested by Cohen-Solal et al. (11): decreases in BNP may be associated with no benefit or even worse outcomes. The SURVIVE trial examined 1,327 patients admitted with worsening HF and low ejection fraction (20). All-cause mortality at 180 days occurred in 26% of the levosimendan treatment arm versus 28% in the dobutamine arm. Although levosimendan-treated patients had a substantial reduction in BNP at 24 h through 5 days when compared to dobutamine, the survival curves demonstrated no statistically significant difference (Figs. 1 and 2).
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Figure 1 Mean Change From Baseline in B-Type Natriuretic Peptide Levels at 1, 3, and 5 Days by Treatment Group
There was significantly greater mean change from baseline in plasma B-type natriuretic peptide levels in the levosimendan group at 1, 3, and 5 days after initiation of study drug infusion. p < 0.001 at all 3 time points. Reproduced, with permission, from Mebazaa et al. (20). Copyright 2007 American Medical Association. All rights reserved.
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Figure 2 Effect of Dobutamine and Levosimendan Treatment on All-Cause Mortality During 180 Days Following the Start of Study Drug Infusion
Reproduced, with permission, from Mebazaa et al. (20). Copyright 2007 American Medical Association. All rights reserved.
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The REVIVE (Randomized Evaluation of Intravenous Levosimendan Efficacy) trials were 2 sequential trials totaling 700 patients, with similar inclusion/exclusion criteria, same duration of infusion, and measurement of BNP at 24 h and at 5 days, similar to the SURVIVE trial (21). Unlike SURVIVE, the REVIVE trials tested levosimendan against placebo. Despite a significant reduction in BNP, use of levosimendan was associated with more adverse events such as ventricular tachycardia (17% vs. 25%), atrial fibrillation (2% vs. 9%), and hypotension (36% vs. 50%). In addition, a trend toward increased mortality was seen during the first 5 days of hospitalization (21). It should be pointed out that the analysis by Cohen-Solal et al. (11) excluded the 69 patients (5.2%) who died within the first 5 days.
Overall, in both the SURVIVE and REVIVE trials, reductions in BNP over 5 days did not translate into improved outcomes. This may be explained by adverse effects of levosimendan, despite reductions in BNP. For example, a significant reduction in SBP and an increase in heart rate was seen with levosimendan, which may have reduced coronary perfusion. The importance of coronary perfusion, particularly in patients with coronary artery disease and AHFS, has been recently recognized (22,23). It is also important to distinguish between prognostic markers and pathophysiologic targets; "improving" a marker may not alter the underlying pathophysiology nor, therefore, the outcomes.
The CAST (Cardiac Arrhythmia Suppression Trial), studying post-myocardial infarction patients with left ventricular dysfunction, provides a historical analogy (24,25). Although post-myocardial infarction ventricular premature beats (VPBs) negatively predict prognosis, active suppression of VPBs by encainide, flecainide, and moricizine in CAST I and II translated into worse outcomes (24,25). It is interesting that during the pre-randomization phase, suppression of VPBs in CAST by these agents was associated with an improvement in long-term outcomes, but only if those therapies were discontinued. The Cohen-Solal et al. (11) findings support the concept that short-term improvement of a prognostic marker, in this case BNP, identifies a population at lower risk. However, this should not be interpreted as a positive response to a specific therapy, in this case levosimendan.
In acute or chronic HF clinical trials, targeting hemodynamics, body weight, serum sodium, neurohormones, or renal function—known predictors of prognosis—have not always been associated with improved clinical outcomes (6,18,26–29) (Table 1). In VMAC (Vasodilation in the Management of Acute Congestive Heart Failure), despite hemodynamic improvement in pulmonary capillary wedge pressure (PCWP), no mortality benefit was seen (6). Furthermore, post-approval concerns arose regarding an increase in mortality (30). The improvement in renal function in response to milrinone in OPTIME-CHF (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) (16,28) was not associated with improved clinical outcomes. In fact, post-discharge mortality was increased in patients with coronary artery disease (23).
The short-term interventions in those examples may hinder extrapolation to long-term outcomes. However, in EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan), rapid and sustained decreases in body weight throughout hospitalization and after discharge without any major side effects did not result in either short- or long-term rehospitalization or mortality benefits (18,31) In retrospect, in the same trial, correction of hyponatremia, a known negative prognostic marker, was not associated with a mortality benefit (32,33). In the MOXSE (Moxonidine Safety and Efficacy) and MOXCON (Moxonidine Congestive HF) studies, significant reductions in norepinephrine, in addition to objective reverse remodeling, did not affect long-term outcomes; in fact, treated patients had an increase in clinical events (27,34). The FIRST (Flolan International Randomized Survival Trial) demonstrated effective decreases in PCWP with epoprostenol (29). Despite a reduction in PCWP being predictive for survival overall, reductions in PCWP by epoprostenol were not associated with improved outcomes (30). Interventions to improve ventricular dyssynchrony in HF provide a welcome contrast. Prolonged QRS duration, a marker of ventricular dyssynchrony and a negative prognostic marker when present despite maximal medical therapy, was successfully targeted by chronic resynchronization therapy resulting in improved long-term outcomes (35,36).
To date, attempts to improve outcomes by targeting HF prognostic markers with pharmacological therapies unknown to affect outcomes have been largely futile. Markers are not mediators, and a marker with one therapy may not be a marker with another therapy with a different mechanism of action. Despite an appropriate choice of marker or pathophysiologic target, untoward drug effects may obfuscate the benefits.
In summary, this retrospective analysis from the SURVIVE trial suggests that short-term reductions in BNP during hospitalizations for HF is associated with an increase in survival post-discharge. However, the hypothesis generated by the authors that reductions in BNP are a reliable surrogate for post-discharge mortality as a result of early therapeutic optimization is not supported by either the SURVIVE or the REVIVE trials; a significant decrease in BNP with levosimendan was not associated with improved outcomes. In fact, there were more adverse events in patients treated with levosimendan and a trend toward worse outcomes. In contrast to the conclusions drawn by Cohen-Solal et al. (11), their data suggest that the overall clinical effect of a given drug cannot be captured by changes of a prognostic marker, since the drug may "improve" the marker by different mechanisms and/or have other potential deleterious effects. In aggregate, the available data suggest that there are no surrogate end points in HF for clinical events such as mortality or rehospitalizations. Although intuitively appealing, for day-to-day clinical practice, extrapolating changes in prognostic markers to outcomes should be done with caution unless therapies known to improve outcomes and/or have a proven safety profile are used to achieve those goals. Given the current absence of such evidence-based therapies in AHFS, a significant therapeutic need exists. Future clinical trials should also refrain from using surrogates as end points; either demonstrate clinical improvement with safety or improve clinical outcomes, irrespective of changes in markers. Nevertheless, the paper by Cohen-Solal et al. (11) raises an important hypothesis that remains to be tested: in patients hospitalized with severe heart failure, a significant decrease in BNP over a few days irrespective of any specific therapy is a better predictor of prognosis than the baseline BNP measurement.
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Acknowledgments
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The authors would like to thank Dr. Gregg Fonarow for his expertise and contribution to this paper.
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Footnotes
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Dr. Gheorghiade is or has been a consultant and/or received honoraria from Abbott, Astellas, Bayer, AstraZeneca, Corthera, DebioPharm, ErreKappa Terapeutici, EKR Therapeutics, GlaxoSmithKline, Johnson & Johnson, Medtronic, Merck, Nile Therapeutics, Novartis, Otsuka, PeriCor Therapeutics, PDL BioPharma, Scios Inc., Solvay Pharmaceuticals, and SigmaTau.
Dr. Pang is or has been a consultant to Astellas, Bayer, The Medicines Company, Otsuka, Nile Therapeutics, PDL BioPharma, Pericor Therapeutics, and Solvay Pharmaceuticals; has received honoraria from BiogenIdec, Corthera, EKR Therapeutics, and Palatin Technologies; and has received research support from Corthera, Merck, and PDL BioPharma.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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