diagnosing acute congestive heart

Diagnosing acute congestive heart failure

Heart failure affects more than 5 million people in the U.S. , 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