Editor's Note: This commentary is based on Balmelli C, Meune C, Twerenbold R, et al. Comparison of the performances of cardiac troponins, including sensitive assays, and copeptin in the diagnosis of acute myocardial infarction and long-term prognosis between women and men. Am Heart J 2013;166:30-37.

Background

While the increase in biomarkers of myocardial necrosis may be delayed in acute myocardial infarction (AMI), the incorporation of the patho-physiologic biomarker copeptin may help in the early detection of AMI. Copeptin, a stable, 39 amino acid glycopeptide degradation product arising from the C-terminal portion of preprovasopressin, provides a better surrogate measurement for arginine vasopressin.¹ Copeptin has been shown to be significantly elevated in patients with AMI,² heart failure,³ shock,⁴ and other life-threatening conditions. Copeptin levels were shown to rapidly rise following myocardial necrosis with a 140% increase within 30 minutes.⁵ Thus, an elevated copeptin level, despite a negative initial troponin, may help identify patients early during AMI, while conversely, a low copeptin level and negative troponin may identify patients who may be safely discharged early from the emergency department (ED). However, previous studies have demonstrated that copeptin levels in healthy volunteers are significantly lower in women than in men,⁶ raising concern whether there are differences in the diagnostic accuracy for acute MI of copeptin for men and women.

Methods

Balmelli, Meune, and colleagues performed analysis of 1,247 patients enrolled in a multi-center international registry who presented to the ED with chest pain and assessed the utility of copeptin and its combination with troponin for the diagnosis and prognosis of AMI and NSTEMI.

Results

They demonstrated that copeptin values were significantly elevated in the 827 men compared with the 420 women (7.7 [interquartile range 4.1 to 15.9] vs. 5.1 [2.9 to 15.7] pmol/L, p=0.001)⁷. There was a trend toward greater diagnostic accuracy for copeptin in women compared with men as assessed by receiver operating characteristic curves for the diagnosis of AMI based on conventional troponin (area under the curve 0.79 [95% CI 0.73 to 0.85] vs 0.73 [95% CI 0.68 to 0.78], respectively, p=0.12). Additionally, there was no difference in diagnostic accuracy between women and men when copeptin was combined with either conventional troponin (0.96 [95% CI 0.94 to 0.98] vs. 0.96 [95% CI 0.94 to 0.97], respectively, p=0.74) or high-sensitivity troponin (0.95 [95% CI 0.93 to 0.98] vs. 0.96 [95% CI 0.94 to 0.97], respectively, p=0.88). Importantly, the addition of copeptin to the initial conventional troponin significantly improved diagnostic accuracy for NSTEMI when compared with the admission troponin alone, regardless of gender (Table II in the manuscript for comparison of area under the ROC curves). However, addition of copeptin to the admission high-sensitivity troponin did not lead to a significant improvement in diagnostic accuracy compared with the admission high-sensitivity troponin (Table II in the manuscript). Finally, a copeptin level ≥14 pmol/L was associated with a worse prognosis (Figure 2C in the manuscript) and had a higher prognostic accuracy than conventional troponin alone, regardless of gender (Table IV in the manuscript)⁷.

Conclusion

The authors concluded that the addition of copeptin to conventional troponin improved diagnostic accuracy for AMI and may provide incremental information as a marker of prognosis. While copeptin is significantly higher in men, there were no significant gender differences in the diagnostic accuracy for copeptin when combined with troponin.

Commentary

Copeptin may not only serve as a marker of AMI, but other severe illnesses, such as acute decompensated heart failure, sepsis, or acute pulmonary embolism. In patients presenting to the ED with chest pain, the addition of copeptin to the initial troponin may help in both diagnostic and prognostic risk stratification, regardless of gender as shown in the highlighted article. The importance of gender cannot be overlooked in patients that present with chest pain to the ED, especially given the known differences in presenting symptoms in women when compared with men. These gender differences are also known to be manifested in biomarkers, as a substudy of TACTICS-TIMI 18, OPUS-TIMI 16, and TIMI 11 demonstrated that men with acute coronary syndrome are more likely to have elevated troponin while women are more likely to have an elevated C-reactive protein and brain natriuretic peptide.⁸ It is reassuring to know that while baseline copeptin levels may be higher in men than women, the diagnostic accuracy for the combination of copeptin and conventional troponin is not significantly different for men and women. This study demonstrated that copeptin may also help identify patients at risk for adverse outcomes. The real utility of copeptin in the ED may be the potential improvement in sensitivity and negative predictive value when added to conventional troponin. For example, an elevation in copeptin may help identify patients in the early stages of AMI who may have a negative troponin on presentation. Though the elevated copeptin may not have such a high positive predictive value for AMI, it may identify patients with serious illness at risk for an adverse outcome. Furthermore, a negative copeptin, in addition to a negative troponin, may help physicians identify patients that may be safely discharged early from the ED. The recent presentation of the BIC-8 trial at the European Society of Cardiology meeting in September 2013 suggested that incorporation of copeptin led to an increase in early discharges from the ED without compromising patient safety. We look forward to seeing whether copeptin will emerge as a biomarker that compliments troponin in early identification of patients with AMI, while helping to safely discharge low-risk patients earlier from the ED, ultimately reducing cost and burden on healthcare providers.

References

1. Morgenthaler NG, Struck J, Alonso C, Bergmann A. Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clin Chem 2006;52(1):112-9.
2. Khan SQ, Dhillon OS, O'Brien RJ, et al. C-terminal provasopressin (copeptin) as a novel and prognostic marker in acute myocardial infarction: Leicester Acute Myocardial Infarction Peptide (LAMP) study. Circulation 2007;115(16):2103-10.
3. Alehagen U, Dahlstrom U, Rehfeld JF, Goetze JP. Association of copeptin and N-terminal proBNP concentrations with risk of cardiovascular death in older patients with symptoms of heart failure. JAMA 2011;305(20):2088-95.
4. Morgenthaler NG, Muller B, Struck J, Bergmann A, Redl H, Christ-Crain M. Copeptin, a stable peptide of the arginine vasopressin precursor, is elevated in hemorrhagic and septic shock. Shock 2007;28(2):219-26.
5. Liebetrau C, Nef H, Szardien S, et al. Release kinetics of copeptin in patients undergoing transcoronary ablation of septal hypertrophy. Clin Chem 2013;59(3):566-9.
6. Bhandari SS, Loke I, Davies JE, Squire IB, Struck J, Ng LL. Gender and renal function influence plasma levels of copeptin in healthy individuals. Clin Sci (Lond) 2009;116(3):257-63.
7. Balmelli C, Meune C, Twerenbold R, et al. Comparison of the performances of cardiac troponins, including sensitive assays, and copeptin in the diagnostic of acute myocardial infarction and long-term prognosis between women and men. Am Heart J 2013;166(1):30-7.
8. Wiviott SD, Cannon CP, Morrow DA, et al. Differential expression of cardiac biomarkers by gender in patients with unstable angina/non-ST-elevation myocardial infarction: a TACTICS-TIMI 18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction 18) substudy. Circulation 2004;109:580-6.

Keywords: Acute Coronary Syndrome, Biomarkers, Amino Acids, C-Reactive Protein, Glycopeptides, Heart Failure, Myocardial Infarction, Natriuretic Peptide, Brain, Patient Safety, Protein Precursors, Pulmonary Embolism, Troponin, Troponin I, Vasopressins, Arginine Vasopressin

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