Diagnosing acute congestive heart failure

Heart failure affects more than 5 million people in the , and 550,000 new cases are diagnosed each year. It is the most common cause of hospitalization in people older than 65 years of age. Approximately 20% of hospitalizations are due to acute congestive heart failure translating into a health-care system cost of $15 billion.

The condition, which can develop as a complication of acute myocardial infarction or as an acute exacerbation in patients with previously compensated chronic heart failure, requires effective diagnostics and improved therapeutics options. As discussed in our recent feature “Chronic and Acute Heart Failure” the late-stage heart failure pipeline is weak in terms of quantity and quality, with almost all candidates being in Phase I and II of development, and the majority of these are being developed for acute heart failure. Thus it is likely that patients will continue to receive current standards of care, primarily anti-diuretics, for the foreseeable future, although ADHERE, the largest registry of acute chronic heart failure patients has made a number of important advances such as underlining the benefits of rapid initiation of vasoactive therapies.

Given the paucity of the pipeline for acute congestive heart failure, the best hope of clinical improvement will involve improved utilization of existing therapies. For example, early initiation of vasoactive therapies can half mortality rates and reduce the need for transfer to ICU/CCU by 80%. This together with a reduction in hospital stay time means that better and earlier uptake of vasoactive therapies will dramatically lower the health-care burden. However early intervention requires rapid and accurate diagnosis. Molecular markers are particularly important for the diagnosis of cardiovascular disease driving a large market in this area (see Cardiac Marker Diagnostic Tests Markets). The measurement of natriuretic peptide levels has driven a significant component of the cardiac molecular diagnostics market.

B-type Natriuretic Peptide (or BNP), also referred to as brain natriuretic peptide, was first identified in 1988. The heart is a major source of circulating BNP which is activated by ventricular distension due to increased intracardiac pressure and is an excellent hormonal marker of ventricular systolic and diastolic dysfunction. BNP levels are related to the severity of signs and symptoms of heart failure and are able to differentiate heart failure from other conditions manifested by dyspnea, one of the primary presenting symptoms of acute heart failure, such as COPD. This is of importance since it can be difficult to distinguish between the two conditions and the use of therapeutics typically used to treat COPD can exacerbate heart failure.

Given its diagnostic potential, the measurement of plasma BNP as an aid in heart-failure diagnosis was approved by the FDA in 2000 and at the time it was suggested that measurement of BNP levels should be part of the diagnostic approach to patients with suspected heart failure. Several BNP assays are now commercialized, including Abbott’s AxSYM; Bayer’s ADVIA; and Biosite’s TRIAGE platforms.

At the time of release from the cardiomyocyte, BNP is co-secreted along with a biologically inert amino-terminal fragment (NT-proBNP) and in 2002, the FDA cleared a NT-proBNP laboratory test for diagnosing congestive heart failure. Sales of assays based on NT-proBNP have overtaken those based on BNP. The leading NT-proBNP diagnostic is Roche Diagnostics’ Elecsys proBNP which has propelled Roche to pole position amongst suppliers of cardiac biomarker assays. In 2005 global sales of Elecsys proBNP reached $760 million. In addition, based on the same antibodies as the Roche proBNP assay, there are now two other NT-proBNP assays either on the market (Dade-Behring) or soon to arrive to market (Ortho Clinical Diagnostics).

Earlier this year James Januzzi and colleagues published the results of a major study including data from four sites in three continents confirming the utility of NT-proBNP as an indicator of acute congestive heart failure (Eur Heart J. 2006 Feb;27(3):330-7). Data recently presented at the AHA suggested that NT-proBNP and BNP have similar accuracy for predicting heart failure in patients; however, NT-proBNP is a better predictor of mortality. This latter point is important since it may allow better identification of high risk patients and thus selection for more intensive monitoring.

Despite the utility of NT-proBNP as a marker of heart failure, the influence of medical illnesses that raise concentrations of NT-proBNP other than heart failure should be considered. In particular, chronic renal disease is associated with increased NT-proBNP levels. It is possible therefore that a patient with chronic renal disease who presents with dyspnea could be falsely diagnosed as having chronic heart failure on the basis of high NT-proBNP levels due to reduced clearance. On the other hand it is possible that already elevated levels due to renal failure are not increased further by co-morbid heart failure. These potential problems are not trivial since a large number of heart failure patients also suffer renal failure. A second study conducted by Januzzi and colleagues and highlighted in the March 28th edition of DailyUpdates thus analyzed data from the PRIDE study, specifically with the aim of evaluating whether NT-proBNP can accurately identify acute congestive heart failure in dyspneic patients across a range of glomerular filtration rates.

As expected, the study demonstrated a significant inverse relationship between renal function and NT-proBNP values in dyspneic patients with and without acute congestive heart failure. However, this relationship was suggested to reflect the presence of underlying structural heart disease and increased plasma volume in patients with chronic kidney disease rather than simply reduced clearance. Furthermore, the study concluded that NT-proBNP was useful for both diagnosing and excluding acute congestive heart failure across a wide spectrum of renal function (with results comparable with those reported for BNP). In addition, regardless of renal function, NT-proBNP maintained its exceptional value for estimation of short-term mortality in congestive heart failure.

A number of specific points are worth highlighting from this PRIDE analysis. Firstly, although NT-proBNP was increased with severity of renal dysfunction, levels were commonly below the cut points for ruling in congestive heart failure as defined in PRIDE. Secondly NT-proBNP levels were significantly higher in patients with congestive heart failure compared to those without across a broad range of glomerular filtration rates. Thirdly, ROC curves (a standard measure of accuracy in diagnostic tests) were not significantly different in patients with high and low glomerular filtration rates although the authors suggest that the cut point at which congestive heart failure can be diagnosed should be increased very slightly from 900 to 1200pg/ml. Notably, at optimal cut-points, the data for NT-proBNP compare rather favorably to those for BNP.This is of particular relevance, as the vendors of the various assays for BNP have been focusing on this topic as an area of possible advantage for BNP over NT-proBNP. The results from PRIDE not only show absolute parity for NT-proBNP with the diagnostic data for BNP from prior studies of patients with impaired renal function, but also extend the understanding of the role of natriuretic peptides in prognostication in those with impaired renal function as well, data that are not available for BNP.

Thus, in conclusion, NT-proBNP measurement is a valuable tool for the diagnostic and prognostic evaluation of dyspneic patients even in the presence of impaired renal function.