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Serial Biomarkers in Heart Failure
Abstract & Commentary
By Michael H. Crawford, MD, Professor of Medicine, and Chief of Clinical Cardiology, at the University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.
Source: Miller WL, et al. Serial biomarker measurements in ambulatory patients with chronic heart failure. Circulation. 2007;116:249-257.
Biomarkers such as brain natriuretic peptides (BNP) and troponin have been shown to be of diagnostic and prognostic value in patients with heart failure, but little is known abut the value of serial outpatient measurements. Thus, Miller and colleagues from the Mayo Clinic studied 200 outpatients with stable NYHA class III-IV heart failure every 3 months for 24 months. Patients awaiting transplant or revascularization and recently unstable patients were excluded. At each visit BNP and troponin T (TNT) were measured. The primary study endpoint was the time until death or transplantation. A secondary endpoint was time to first hospitalization for decompensated heart failure. The goal of the study was to compare these endpoints over time to the biomarker measures. TNT above the upper limit of normal exhibited at 3.4-fold increase in the risk of an endpoint (P < 0.02). Further increases on serial measurements increased this risk to 5 fold (p < 0.001). A BNP greater than the 95% percentile in normal individuals increased risk 5 fold (p < 0.001), but further increases over time did not change risk. If both biomarkers were elevated, the risk increased to 8.6 fold (p < 0.001). However, once the TNT is > 0.03 mg/mL, then an elevated BNP does not add to the risk. The authors concluded that elevated TNT or BNP at any time during the outpatient follow-up of class III-IV heart failure patient predicts an increased risk of a cardiac event. Further increases in TNT augment this risk. The authors suggest that serial outpatient measurements of biomarkers contribute important information for the management of heart failure patients.
Biomarkers have proven useful for diagnosis, but their role in chronic disease management is less clear. Because of the challenge of determining fluid volume status in chronic heart failure patients, it was hoped that BNP measurements would aid in this clinical decision. In acutely decompensated patients, reductions in BNP appear to correlate with the improving condition of the patient, but what about the outpatient setting? This study would suggest BNP is of limited value. In their stable outpatients with moderate to severe heart failure, about two-thirds already had an elevated BNP (above 95th percentile for age and sex) and these patients did less well than those with normal values, but further increases in BNP did not predict events. Thus, BNP could be measured once in a stable outpatient to see if they are in a higher risk group, but serial measurements seem unjustified.
Surprisingly, TNT was predictive of a poor outcome and further rises predicted events and decreases predicted lower risk. About half of their patients had an elevated TNT at baseline (> 0.01 ng/mL) and 28% had values > 0.03 ng/L. The combination of an elevated BNP and TNT carried the greater risk of an event unless TNT was > 0.03 ng/mL. These results suggest that both BNP and TNT should be measured once in stable outpatients with moderate to severe heart failure and then consider re-measuring TNT if there is concern that the patient may be deteriorating. Further elevations in TNT may identify patients who should be listed for transplant.
Why does TNT predict events in stable outpatients with heart failure? It is unclear, but there are several possibilities. Perhaps TNT is measuring apoptosis of cardiac cells and when this accelerates the patient is worsening. Since most patients with heart failure have ischemic heart disease, perhaps TNT detects microinfarcts that herald worsening of heart failure. However, there did not seem to be a difference between patients with different etiologies and the predictive power of TNT, suggesting that worsening heart failure may be due to "heart failure infarcts" that are related to increased cytokines and inflammation.
Two caveats to the use of these biomarkers in heart failure patients: BNP is inversely related to body mass index and TNT is directly related to glomerular filtration rate. These factors have to be taken into consideration when evaluating the significance of single measurements.