Unstable Angina: New Markers for Prognosis

Abstracts & Commentary

Synopsis: Brain natiuretic peptide and pregnancy-associated plasma protein show promise as a marker for unstable angina prognosis.

Sources: De Lemos J, et al. N Engl J Med. 2001; 345:1014-1021; Bayes-Genis A, et al. N Engl J Med. 2001;345:1022-1029.

Timi 16, a large, randomized, controlled trial assessing the oral IIb/IIIa inhibitor orbofiban, included a sub-study measuring brain (B-type) natriuretic peptide (BNP) at baseline in 2500 individuals hospitalized with an acute coronary syndrome. The study population included patients with MI with and without ST segment elevation, as well as those with unstable angina. The end points included death or nonfatal MI at 30 days and 10 months. Baseline BNP, when adjusted for multiple other factors, including C-reactive protein, was highly predictive of clinical outcomes. Using quartiles of BNP, mortality was strongly related to this neurohormone (P < 0.001), and was correlated with a variety of adverse outcomes, including death, new or progressive heart failure, or recurrent MI at 30 days and 10 months. BNP levels were obtained approximately 2 days after hospitalization and before randomization to orbofiban or placebo. De Lemos and associates established a cut-point of 80 pg/mL, and demonstrated that patients with a BNP level < 80 had a substantially more benign prognosis than those with a level > 80 pg/mL (P = 0.04). Increasing levels of BNP correlated with worse outcomes, irrespective of a variety of other risk markers, including hs-CRP and ECG changes. De Lemos et al conclude, "these findings suggest that B-type natriuretic peptide should be measured after an acute coronary syndrome in order to identify patients with high and low risk for adverse outcomes and that treatment, including the intensity of surveillance and the use of aggressive pharmacologic interventional therapy, should be adjusted accordingly."

Another report in the same issue of the New England Journal of Medicine involves a brand new risk factor, pregnancy-associated plasma protein A (PAPP-A), as a marker for unstable atherosclerotic plaque in individuals with unstable angina. This molecule has previously been identified as an inflammatory component of unstable plaque. This pilot study from the Mayo Clinic attempts to evaluate whether serum levels of PAPP-A can predict clinical outcomes. In addition to examining expression of PAPP-A in culprit plaques in subjects who died suddenly of cardiac cause, they assessed levels of this compound, CRP, and insulin-like growth factor (IGF) in 17 patients with acute MI, 21 with unstable angina, 19 with stable angina, and 13 controls. PAPP-A levels correlated with adverse outcomes in unstable angina and acute MI patients; Bayes-Genis and colleagues conclude that this molecule may be useful as a diagnostic marker for acute coronary syndromes that is "better than C-reactive protein." A threshold PAPP-A level of 10 mIU had an excellent sensitivity and specificity for ACS and "accurately identified patients" with 1 of these syndromes. PAPP-A did not correlate with troponin I and CK-MB levels, indicating that PAPP-A is not produced by necrosis, but rather is an inflammatory marker. The compound is a metallo-proteinase, and generally correlated with levels of CRP. PAPP-A is the enzyme that clears IGF binding protein, although IGF levels were not useful in this report. They conclude, "that PAPP-A is a new candidate marker for the early diagnosis of acute coronary syndromes, and that it can identify patients early in the process of plaque instability."

Comment by Jonathan Abrams, MD

PAPP-A is a fascinating discovery, which could turn out to be of importance. Although only a small number of individuals were evaluated, this is a provocative observation that should be vigorously pursued. Information regarding the ease and reproducibility of the assay are not provided. Clearly, future reports will be awaited with great interest. On the other hand, the use of BNP for individuals hospitalized with chest pain demonstrates great promise, based on the report from TIMI 16. This compound has already been shown to have major prognostic implications in congestive heart failure, and is also elevated in acute myocardial infarction. Whether BNP rises and does or does not fall rapidly also has prognostic import. This analysis indicates that BNP might be a highly reliable risk marker in a variety of ACS, including STEMI, NSTEMI, and unstable angina. The cut point of 80 pg/mL is concordant with the experience in congestive heart failure. While a single report cannot change clinical practice, the statistical power and independence of this marker is intriguing, and the fact that commercial assays are now available suggests that BNP assessment in a variety of cardiovascular syndromes, not only congestive heart failure, may become common in the future. Clearly, other data are needed to confirm the TIMI 16 observations. Nevertheless, the independence from troponin I, the ECG, and other clinical factors supports the view that the BNP assay may turn out to be extremely valuable.