Evaluation of Multiple Biomarkers of Cardiovascular Stress for Risk Prediction and Guiding Medical Therapy in Patients With Stable Coronary Disease

Study Questions:

Do biomarkers related to volume status or pressure overload aid in predicting adverse events and response to angiotensin-converting enzyme (ACE) inhibition?

Methods:

Four cardiovascular (CV) biomarkers (midregional pro-atrial natriuretic peptide [MR-proANP], midregional pro-adrenomedullin [MR-proADM], C-terminal pro-endothelin-1 [CT-proET-1], and copeptin) were measured in 3,717 patients with stable coronary artery disease (CAD) and preserved ejection fraction (EF) who were randomized to trandolapril or placebo as part of the PEACE (Prevention of Events With Angiotensin Converting Enzyme) trial.

Results:

Elevated levels of MR-proANP, MR-proADM, and CT-proET-1 were independently associated with the risk of CV death or heart failure (HF) (hazard ratios per 1-standard deviation increase in log-transformed biomarker levels of 1.97, 1.48, and 1.47, respectively; p ≤ 0.002 for each biomarker). These three biomarkers also significantly improved metrics of discrimination when added to a clinical model. Trandolapril significantly reduced the risk of CV death or HF in patients who had elevated levels of ≥2 biomarkers (hazard ratio, 0.53; 95% confidence interval, 0.36-0.80), whereas there was no benefit in patients with elevated levels of 0 or 1 biomarker (hazard ratio, 1.09; 95% confidence interval, 0.74-1.59; Pinteraction = 0.012).

Conclusions:

In patients with stable CAD and preserved EF, these results suggest that elevated levels of novel biomarkers of cardiovascular stress may help identify patients who are at higher risk of CV death and HF, and may be useful to select patients who derive significant benefit from ACE inhibition.

Perspective:

In the PEACE trial, patients with CAD and preserved left ventricular EF did not benefit from ACE inhibition. These results were contrary to previous trials with ACE inhibition (i.e., the HOPE trial), and may have been due to the relatively low risk of events in the PEACE patient population. The current study is consistent with this hypothesis, and demonstrates that further risk stratification of the PEACE population with biomarkers reflective of pressure overload may be useful to identify a high-risk subpopulation that benefits from ACE inhibition. Additional prospective trials are needed to validate these intriguing observations.

Clinical Topics: Anticoagulation Management, Heart Failure and Cardiomyopathies, Atherosclerotic Disease (CAD/PAD), Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Coronary Artery Disease, Endothelin-1, Adrenomedullin, Peptidyl-Dipeptidase A, Heart Diseases, Biological Markers, Cardiology, Indoles, Heart Failure, Peptide Fragments, Heart Ventricles, Atrial Natriuretic Factor


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