The ADHERE classification and regression tree model overestimates mortality rates in clinical trials: results from REVIVE I & II

Background

Blood urea nitrogen (BUN), systolic blood pressure (SBP), and serum creatinine (Cr) were significant predictors of inhospital mortality by classification and regression tree (CART) analysis of ADHERE. REVIVE I & II (REVIVE) compared levosimendan with placebo, in addition to standard-of-care (SOC), in patients with acute decompensated heart failure. We hypothesized that mortality in REVIVE would be similar to ADHERE in all CART-defined risk subgroups.

Methods

REVIVE (n = 700) mortality data were mapped using the same variables/cut-points as the ADHERE CART analysis.

Results

Compared with ADHERE, proportionately more patients in REVIVE had SBP <115 mmHg (56.4% vs 18.6%; P < 0.001) with more patients (3.0% vs 1.9%; P < 0.05) in the highest mortality risk subgroup (SBP <115 mmHg, BUN ≥ 43 mg/dl, and Cr ≥ 2.75 mg/dl). For the total population and for every CART-defined subgroup, REVIVE inhospital mortality rates were lower than those from ADHERE. See Figure 1.

Figure 1

Mortality rates from REVIVE for subgroups defined by the ADHERE classification and regression tree model.

Conclusion

Clinical trials (REVIVE) may enroll proportionately more patients at increased risk of mortality in comparison with the general population (ADHERE). Despite the predicted increased mortality risk, mortality rates were lower in REVIVE than in ADHERE for the total population and for every CART-defined risk subgroup. Differences in SOC or additional risk factors, such as age or other comorbid conditions, may contribute to the poorer prognosis in nontrial populations.