Biomarker Predicts Risk in Stable Coronary Heart Disease

SAN FRANCISCO, Jan 9 -- B-type natriuretic peptide, a marker of myocardial stretch, predicted adverse coronary outcomes and mortality in patients with stable coronary heart disease, researchers reported.

Elevated levels of the N-terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP) predicted all-cause mortality, coronary-artery-disease mortality, stroke, and events related to heart failure, Kirsten Bibbins-Domingo, Ph.D., M.D., of the University of California San Francisco, and colleagues, reported in the Jan. 10 issue of the Journal of the American Medical Association.

Patients with stable disease having the highest concentrations NT-proBNP had an eightfold unadjusted increased rate of cardiovascular events or death compared with those with the lowest levels. Even after adjustment for other prognostic markers, the risk of an adverse outcome was three times higher,

These findings seem to conflict with those of a Framingham study reported a month ago in which Harvard researchers found that B-type natriuretic peptide, evaluated along with other biomarkers, added little substance to standard cardiovascular risk factors.

The California findings came from a prospective cohort study (2000 to 2002) of 987 ambulatory individuals in California with stable coronary heart disease in the Heart and Soul study who were followed up to a mean of 3.7 years (range 0.1-5.3). Outpatients were recruited from two California VA databases, one university medical center, and nine public health clinics.

Traditional clinical risk factors, ECG measures, ischemia, other biomarkers, and the New York Heart Association classification were used to determine whether NT-proBNP levels were independent of other prognostic factors. Receiver operating characteristic (ROC) curves assessed the incremental prognostic value of adding NT-proBNP level to these other measures.

Self-reported age, sex, ethnicity, medical history, and smoking status were determined by questionnaire. The mean NT-proBNP level among the 987 participants was 174.8 pg/mL.

Although coronary heart disease was stable, participants in the highest quartile were older (age 72 versus 61), had more significant disease, such as diabetes, and were more likely to have clinical risk factors for adverse cardiovascular events, including hypertension, MI, or revascularization, higher systolic blood pressure, lower creatinine clearance, and higher C-reactive fractions. They were also more likely to be taking beta-blockers, renin-angiotensin inhibitors, and statins.

Among the findings: A total of 256 participants (26.2%) had a cardiovascular event or died. Each increasing quartile of NT-proBNP level was associated with a greater risk of cardiovascular events or death. Those in the highest quartile had an unadjusted 7.8-fold increased rate of a cardiovascular event or death compared with those in the lowest quartile.

The quartile ranges were quartile 1, range 8.06-73.95 pg/mL; quartile 2, 74-174.5 pg/mL; quartile 3, 175.1-459 pg/mL; quartile 4, ?460 pg/mL).

Rates ranged from 23 of 247 (annual event rate, 2.6%) in the lowest quartile to 134 of 246 (annual event rate, 19.6%) in the highest quartile (unadjusted hazard ratio [HR] for quartile 4 versus quartile 1, 7.8; 95% confidence interval [CI], 5.0-12.1; P

Also, they said, incident heart failure was defined by hospitalization so that individuals who were diagnosed and treated for new-onset heart failure in an outpatient setting may not have been captured in this analysis, suggesting that the results may have been biased toward the detection of more acute presentations of heart failure.

In an interview, Carl Lavie, M.D., medical director of cardiac rehabilitation and prevention and director of the stress testing laboratory at Ochsner Health System in New Orleans, pointed out that not surprisingly the patients with high levels of NT-proBNP had high levels of traditional risk factors, including poor health and a range of cardiovascular risk factors.

Dr. Lavie noted that the eightfold increased risk dropped to a still significant threefold greater risk after correcting for a host of known cardiac risk measures. However, he said that these are statistical adjustments, and it is not easy to determine how much statistical adjustment one should give for findings.

Addressing the clinical implications of the study, Dr. Lavie said, "If I had a patient who had maxed out on all treatment possibilities, there would be no point in determining that person's BNP. However, if my patient had received standard therapy, and I found the BNP very high, I would try to intensify therapy."

As a gauge to further intensify medical treatment," Dr. Lavie said, "we now need a study to find whether determining BNP leads to a reduction of events."

In an editorial in the same issue, Marvin Konstam, M.D., of Tufts New England Medical Center in Boston, wrote that prior investigations had identified plasma BNP and NT-proBNP levels as independent predictors of mortality and cardiovascular events in populations with chronic heart failure, acute coronary syndromes, prior myocardial infarction, established vascular disease, and elevated coronary risk.

This study, he said, extends these observations within a population of patients with stable disease and further clarifies the utility of NT-proBNP level as a predictor of a variety of subsequent cardiovascular events. Furthermore, he said, these findings provoke reconsideration of the value of these markers as diagnostic tools and potentially as triggers for therapeutic intervention.

However, before accepting the proposal that NT-proBNP be used to screen patients and be considered for therapeutic intervention, it is important to note that the use of a biomarker for triggering or guiding therapy requires more than the demonstration of its correlation with worse clinical outcomes.

Despite the predictive value of NT-proBNP, the clinical utility of screening patients with stable coronary artery disease is uncertain, Dr. Konstam wrote. On the basis of current evidence, treatment with an angiotensin-converting enzyme inhibitor, aspirin, and statins is already recommended in most of these patients, while beta-blockers are recommended for those with prior myocardial infarction or with reduced left ventricular ejection fraction.

Nevertheless, Dr. Konstam said, the findings of the Bibbins-Domingo study and those of other studies suggest that screening with BNP levels would be cost-effective for populations with a 1% prevalence of reduced left ventricular ejection fraction.

Although the relationship between plasma NT-proBNP and cardiovascular risk may be driven partly through myocardial stretch, it is likely that these levels are also influenced by left ventricular mass and fibrosis, myocardial ischemia, and levels of neurohormones and inflammatory cytokines, he wrote.