Prospective Evaluation of Pregnancy-Associated Plasma Protein-A and Outcomes in Patients With Acute Coronary Syndromes

Study Questions:

Does pregnancy-associated plasma protein-A (PAPP-A) predict risk for non–ST-segment elevation acute coronary syndrome (NSTE-ACS)?


Patients used for this study were enrolled in the MERLIN–TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) trial. Participants were randomized to ranolazine or placebo in a 1:1 ratio and followed for a median of 348 days. PAPP-A was measured at baseline in all available samples (n = 3,782) using a highly sensitive assess to detect low concentrations in nonpregnant men and women. A cut point of 6.0 µIU/ml was chosen for this pilot study. The primary endpoints of interest were cardiovascular (CV) death or myocardial infarction (MI).


Participants with PAPP-A ≥6.0 µIU/ml were older, more frequently male, and more likely to have a creatinine clearance <60 ml/min, but were less likely to have diabetes, hypertension, or dyslipidemia. PAPP-A ≥6.0 µIU/ml, measured at baseline was associated with higher rates of CV death or MI at 30 days (7.4% vs. 3.7%; hazard ratio [HR], 2.01; 95% confidence interval [CI], 1.43-2.82; p < 0.001) and at 1 year (14.9% vs. 9.7%; HR, 1.63; 95% CI, 1.29-2.05; p < 0.001). Individual outcomes (CV death and MI) were both significantly associated with PAPP-A level. There was no difference in the risk associated with PAPP-A stratified by baseline cardiac troponin I. After adjustment for cardiac troponin I, ST-segment deviation, age, sex, diabetes, smoking, hypertension, and coronary artery disease, PAPP-A was independently associated with CV death/MI at 30 days (HR, 1.62; 95% CI, 1.15-2.29; p = 0.006) and 1 year (HR, 1.35; 95% CI, 1.07-1.71; p = 0.012). PAPP-A also improved the net reclassification for CV death/MI (p = 0.003). There was no significant interaction with ranolazine.


The investigators concluded that PAPP-A is independently associated with recurrent CV events in patients with NSTE-ACS events. This suggests the use of PAPP-A as a prognostic marker for adverse outcomes, specifically CV death and recurrent MI.


Metalloproteinases such as PAPP-A may add value as prognostic markers for poor outcomes. Further research is warranted to determine the clinical value of markers such as PAPP-A.

Clinical Topics: Prevention, Atherosclerotic Disease (CAD/PAD), Hypertension, Smoking

Keywords: Myocardial Infarction, Coronary Artery Disease, Piperazines, Neurofibromin 2, Creatinine, Smoking, Biological Markers, Troponin I, Metalloproteases, Hypertension, Pregnancy-Associated Plasma Protein-A, Diabetes Mellitus

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