An Aggregate Biomarker Risk Score Predicts High Risk of Near-Term Myocardial Infarction and Death: Findings From BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes)

Abstract

Background: In a previous study, we found that a biomarker risk score (BRS) comprised of C-reactive protein, fibrin-degradation products, and heat shock protein-70 predicts risk of myocardial infarction and death in coronary artery disease patients. We sought to: (1) validate the BRS in the independent BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) cohort, (2) investigate whether 1 year of intensive medical therapy is associated with improved BRS, and (3) elucidate whether an altered BRS parallels altered risk.

Methods and results: Two thousand thirty-two subjects with coronary artery disease were followed for 5.3±1.1 years for cardiovascular events. Biomarkers were measured at baseline and retested in 1304 subjects at 1 year. BRS was determined as the biomarker number above previously defined cut-off values (C-reactive protein >3 mg/L, heat shock protein-70 >0.313 ng/mL, and fibrin-degradation products >1 μg/mL). After adjustment for covariates, those with a BRS of 3 had a 4-fold increased risk of all-cause death and a 6.8-fold increased risk of cardiac death compared with those with a BRS of 0 (95% CI, 2.9-16.0; P<0.0001). All individual biomarkers decreased by 1 year, with ≈80% of patients decreasing their BRS. BRS recalibrated at 1 year also predicted risk. Those with 1-year BRS of 2 to 3 had a 4-year mortality rate of 21.1% versus 7.4% for those with BRS of 0 to 1 (P<0.0001).

Conclusions: Our results validate the ability of the BRS to identify coronary artery disease patients at very high near-term risk of myocardial infarction/death. After 1 year of intensive medical therapy, the BRS decreased significantly, and the reclassified BRS continued to track with risk. Our results suggest that repeated BRS measurements might be used to assess risk and recalibrate therapy.

Keywords: biomarker; coronary artery disease; major adverse cardiovascular event; risk score.

Figure 1

Flow chart demonstrates number of subjects at baseline and 1‐year time points with available biomarker samples. BARI 2D indicates Bypass Angioplasty Revascularization Investigation 2 Diabetes; BRS, biomarker risk score.

Figure 2

Kaplan–Meier cumulative incidence curves by BRS score. A through D, Demonstrate this association with all‐cause death, cardiac death, composite death/MI, and death/MI/revascularization, respectively, in those with BRS of 0, 1, 2, and 3. BRS, biomarker risk score; LR, likelihood ratio; MI, myocardial infarction; Subseq., subsequent.

Figure 3

Sensitivity analysis of the biomarker risk score in association with death/MI outcome with respect to individual covariates. GFR indicates glomerular filtration rate; IP, insulin‐providing; IS, insulin‐sensitizing; LVEF, left ventricular ejection fraction; MED, medical therapy; MI, myocardial infarction; MJI, myocardial jeopardy index.

Figure 4

Calibration plots for the multivariable Cox Models for the predicted probability of an event 4 years after randomization. The calibration plots correspond to the multivariable adjusted Cox model 3 shown in Table 3 for all‐cause death (A), cardiac death (B), death/MI (C), and death/MI/revascularization (D). Each bar represents ≈10% of the patients rank ordered based on their predicted probability of an event from the Cox model (ie, deciles of risk). The height of the bar is the observed proportion of patients who had an event by 4 years. MI indicates myocardial infarction.

Figure 5

Kaplan–Meier cumulative incidence curves by the biomarker risk score measured in survivors at 1‐year postrandomization. A through D, Demonstrate this association with all‐cause death, cardiac death, composite death/MI, and death/MI/revascularization, respectively. LR indicates likelihood ratio; MI, myocardial infarction.

Figure 6

Kaplan–Meier death/MI cumulative incidence curve in those with the biomarker risk score of 2 to 3 at baseline. A, Demonstrates the death/MI event curve during the first year of follow‐up. B, Demonstrates event rates from years 2 to 5 in subjects in whom the BRS decreased to 0 or 1 compared with those in whom the BRS remained high at 2 or 3. MI indicates myocardial infarction.