Increased 90-Day Mortality in Acute Heart Failure Patients With Elevated Copeptin: Secondary Results for the Biomarkers in Acute Heart Failure (BACH) Study

Study Questions:

Serum copeptin is the C-terminal segment of pre-pro-vasopressin. Do serum copeptin levels correlate with adverse outcome in patients with acute heart failure (HF)?

Methods:

Serum levels of copeptin, B-type natriuretic peptide (BNP), N-terminal pro-BNP (NT-proBNP), and sodium were measured in 557 patients presenting to 1 of 15 medical centers with acute HF as part of the BACH study. The primary outcome of interest was the combined endpoint of 90-day mortality, readmission for HF, or emergency room visits for HF. Receiver operator characteristic (ROC) curves were used to assess marker discrimination and to identify an optimal copeptin cutoff for predicting outcome.

Results:

At 90 days, there 64 (11%) deaths; 149 combined deaths or HF-related admissions (27%); and 172 combined deaths, HF-related admissions, or emergency visits (31%). Patients who died were older (mean ± standard deviation = 75 ± 12.8 vs. 70.7 ± 13.9 years), had lower systolic blood pressure (129 ± 30 vs. 145 ± 32 mm Hg), a lower body mass index (BMI; 24.8 ± 5.2 vs. 29 ± 8.3), higher serum creatinine (median [25th, 75th] = 1.4 [0.98, 2.1] vs. 1.2 [0.91, 1.6] mg/dl), and lower serum sodium (137 [133, 40] vs. 139 [137, 141] mEq/L) than survivors. Deaths also had higher serum BNP (1041 [501, 2337] vs. 718 [371, 1343] ng/L), NT-BNP (9227 [4098, 17,261] vs. 4717 [2055, 9430] ng/L), and copeptin (55 [20, 114] vs. 24 [10, 52] pmol/L) levels than survivors, respectively (all p ≤ 0.005). When mortality was assessed by copeptin deciles, most of the deaths occurred in quartiles 8-10. Only the highest (56-1115 pmol/L) versus lowest (1.1-10.7 pmol/L) copeptin quartile comparison was significant (hazard ratio [HR] for mortality, 3.85 [1.8, 8.1], p < 0.001). The areas ± standard error under the ROC curves for BNP, NT-BNP, and copeptin were 0.61 ± 0.04, 0.67 ± 0.04, and 0.66 ± 0.04, respectively. The copeptin cutpoint of 38.5 pmol/L was determined to be the best discriminator of death based on ROC analysis. When adjusting for systolic blood pressure, BMI, sodium, NT-proBNP, and logCreatinine, the risk of death was 2.0 [1.1-3.8] fold higher for patients with a copeptin level >38.5 pmol/L. Compared with patients with a serum sodium >135 mg/dl and copeptin <26.99 pmol/L (sample median), patients with a sodium ≥135 mEq/L and copeptin ≥26.99 pmol (HR, 1.41 [1.00, 1.97], p = 0.049) and patients with a sodium ≤135 mEq/L and copeptin ≥26.99 pmol/L (HR, 3.87 [2.41-6.20], p < 0.001) had a higher risk of death.

Conclusions:

The authors concluded that elevated copeptin is associated with worse outcome in patients presenting with acute HF, especially in those with low serum sodium.

Perspective:

Given the high prevalence of HF and the burden of HF readmissions on the health care system, a means of identifying which patients with acute HF will have the worst outcome would be useful. Several biomarkers including BNP, NT-BNP, cystatin C, and b-trace protein have been correlated with acute HF death. In this study, the vasopressin axis of HF modulation was studied through measurement of the ADH precursor copeptin. Interestingly, serum sodium did not correlate with copeptin levels. However, patients with high copeptin levels and low serum sodium had worse outcome than those with high copeptin levels and normal serum sodium (hyponatremia and elevated copeptin were an additive effect). As the authors point out, this may be useful when considering the addition of vasopressin antagonists to HF therapy. Given the low area under the curve of copeptin and nonlinear impact of copeptin levels on outcome, more studies are needed to best determine if and how this marker will add to HF management and risk stratification.

Clinical Topics: Anticoagulation Management, Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Survivors, Prevalence, Hyponatremia, Vasopressins, Biological Markers, Sodium, Protein Precursors, Heart Failure, Blood Pressure


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