B·R·A·H·M·S Copeptin proAVP: Cardiology

Laboratory test for myocardial infarction: Early rule-out of AMI

In this era of overcrowded emergency departments (EDs), measuring Copeptin along with cardiac Troponin (cTn) or high sensitive cardiac Troponin (hscTn) in the first blood draw can help safely increase ED discharge and decrease hospital and ED/chest pain unit (CPU) lengths-of-stay in patients presenting with signs and symptoms of Acute Coronary Syndrome (ACS). 

The benefits of implementing Copeptin testing for rule-out of myocardial infarction

ED overcrowding is a major problem significantly linked to:

  • More frequent death or adverse cardiovascular outcomes in patients hospitalized for chest pain or for related possible cardiac complaints2
  • Increased mortality at 2 days 3, 7 days3-4, and 30 days3
  • Decreased adherence to guideline-recommended therapies and higher risk of recurrent MI in patients with non-ST-segment evaluation myocardial infarction (NSTEMI)5
  • Delayed intravenous thrombolysis in patients with suspected AMI6

Fast, accurate AMI rule-out can help:

  • Better target monitoring and interventions to the ~10% of chest pain patients truly having AMI
  • Avoid unnecessary monitoring, treatment, discharge waits, and anxiety in the ~90% of chest patent patents without AMI18
  • Optimize patient management in the ED
  • Optimize resource allocation and processes at patients hospital stay
  • Improve patient risk stratification

BIC-8 interventional trial

The Biomarkers in Cardiology (BIC)-8 study was the first interventional clinical trial in the cardiac biomarker field, and it confirms the safety and efficacy of the combined use of Copeptin and Troponin in patients with ACS.1

 

BIC-8 interventional trial
BIC-8 interventional trial

Results

  • Achieved a 5.6-fold increase in ED discharge rate: 67.6% in the Copeptin arm vs. 12.0% in the conventional arm (P<0.001)
  • Achieved a >40% reduction in hospital length-of-stay: Median 4 hours in copeptin arm vs. 7 hours in the conventional arm (P<0.001)
  • Achieved a >40% reduction in ED/CPU length-of-stay in patients not admitted to wards or intensive care units, shortening the patient’s time in ED by 3 hours: Median 4 hours in the Copeptin arm (n-384) vs. 7 hours in the conventional arm (n=383) (P<0.001)
  • Preserved safety:
    o   30-day major adverse cardiovascular event (MACE) rate in copeptin arm was low and non-inferior to that of the conventional arm
    o   No 30-day mortality occurred in the Copeptin arm

ED discharge rate

Preserved patient safety

*The BIC-8 study defined major cardiovascular adverse events as any death from any cause, survived sudden cardiac arrest, re-hospitalization for acute coronary syndrome (ACS), acute unplanned percutaneous coronary intervention, coronary artery bypass grafting, or documented life-threatening arrhythmias. 

Safety and efficacy

In low-to-intermediate-risk patients, the Copeptin + Troponin rapid AMI rule-out concept demonstrated very high safety in the multicenter, multinational prospective, randomized, controlled interventional Biomarkers in Cardiology-8 (BIC-8) study.1 described as “seminal” in an European Heart Journal editorial.7 Additionally, the concept has shown very high negative predictive values (NPVs), that is, rates of correct rule-out, in numerous prospective observational studies.

 

However, patients with negative Copeptin plus negative Troponin should not be sent home automatically. As indicated by the clinical assessment, the physician may need to further investigate the underlying reasons for the symptoms (which may be life-threatening even if unrelated to AMI).

 

In BIC-81, 67.6% of patients in the Copeptin + Troponin study arm was discharged from the emergency department (ED) without need for protracted ED monitoring or in a chest pain unit (CPU). That rate was 5.6-fold higher than the 12.0% ED discharge rate seen in the conventional process study arm (P<0.001). In the conventional process arm, Copeptin data were NOT used to help guide management, and patients with a negative Troponin at presentation typically had to undergo repeat Troponin testing and other protracted monitoring including the performance of several electrocardiography (ECG) tests. 

Data from BIC-81 suggests that this combination correctly rules out acute myocardial infarction (AMI) in the vast majority of patients. For example, a meta-analysis8 of 14 prospective observational studies involving 9,244 patients in total found the Copeptin + Troponin strategy to have a negative predictive value (NPV) of 97.0%, i.e., a 97% correct rule-out. This rate represented a significant improvement over Troponin alone (P < 0.001).

Test interpretation 

In the setting of suspicion of AMI, an elevated copeptin value means that this condition cannot be ruled out. An elevated Copeptin value with a simultaneous negative troponin value indicates the need for serial troponin measurement. Clinicians of course should be aware that with Copeptin, as with all biomarkers, values should be considered in the context of concomitant comprehensive clinical assessment, including electrocardiography in the case of suspected acute coronary syndrome (ACS).

Whether chest pain is present or not, an AMI would be expected to produce sufficient hemodynamic stress to induce Copeptin elevation. The Copeptin rise is most likely stimulated by endogenous stress and is not related to the sensation of physical pain.

Literature regarding the effects of alcohol12 or nicotine or cigarette smoking on vasopressin13-15, for which Copeptin is a 1:1 surrogate, suggests that drinking alcoholic beverages decreases copeptin levels, whereas cigarette smoking increases Copeptin levels. However, these changes appear generally to be of much smaller magnitude than those related to AMI, and therefore would be expected to seldom if ever confound interpretation of Copeptin results in AMI rule-out.

Clinical use 

The results of BIC-81 as well as a variety of earlier studies10,11,16,17 suggest that low to intermediate risk patients (GRACE score ≤140) with negative Copeptin and negative Troponin at presentation may be safely discharged from the emergency department – but only if warranted by comprehensive clinical assessment. As with any biomarker, Copeptin and Troponin biomarkers should never be used in isolation to guide patient management. 

To rule out AMI in low-risk to intermediate-risk patients, a second troponin measurement is unnecessary when:

  • The initial measurements of Troponin and Copeptin BOTH are below institutional cut-offs for AMI rule-out.
  • There is no further suspect of myocardial infarction due to the clinical presentation of the patient.

Copeptin, a marker of severe hemodynamic stress, is elevated very soon after AMI onset. Depending on the Troponin assay sensitivity, Troponin, a marker of cardiac necrosis, typically has a 3–6 hr delay after symptom onset for cTn or at least a 1hr delay after symptom onset for hscTn before circulating levels rise above the cut-off for positivity (‘Troponin-blind period or Troponin diagnostic gap). Because AMI involves both, severe hemodynamic stress and cardiac necrosis, the condition almost invariably results in elevation of one or both of Copeptin or Troponin, regardless of how long after symptom onset. Consequently, AMI can be excluded with very high probability if both markers are negative at the time of admission with only one blood draw

 

Figure: Release kinetics of Copeptin vs other markers (Gu YL et al. 2011)

Explore Copeptin utility for endocrinology and electrolyte/vasopressin dependent disorders.

Reference

1.     Möckel M et al. Eur Heart J. 2015;36(6):369–376.

2.     Pines JM et al. Acad Emerg Med. 2009;16:617–625. DOI: 10.1111/j.1553-2712.2009.00456.x.

3.     Sprivulis PC et al. Med J Aust. 2006;184:208–212.

4.     Guttmann A et al. BMJ. 2011;342:d2983. DOI: 10.1136/bmj.d2983.

5.     Diercks DB et al. Ann Emerg Med. 2007;50:489–496. DOI: 10.1016/j.annemergmed.2007.03.033.

6.     Schull MJ et al. Ann Emerg Med. 2004;44:577–585. DOI: 10.1016/S0196064404005232.

7.     Gandhi & Januzzi. Eur Heart J. 2014. DOI: 10.1093/eurheartj/ehu211.

8.     Lipinski et al. Am J Cardiol. 2014;113(9):1581–1591.

9.     Stallone et al. Heart. 2014. DOI: 10.1136/heartjnl-2014-305583.

10.  Reichlin et al. J Am Coll Cardiol. 2009;54(1):60–68.

11.  Keller et al. J Am Coll Cardiol. 2010;55(19):2096–2106.

12.  Wright. Clin Endocrinol Metab. 1978;7(2):351–367.

13.  Goldsmith et al. Clin Pharmacol Ther. 1988;44(4):478–481.

14.  Chiodera et al. Acta Endocrinol (Copenh). 1990;123(5):487–492.

15.  Netscher et al. Plast Reconstr Surg. 1995;96(3):681–688.

16.  Khan et al. Circulation. 2007;115(16):2103–2110.

17.  Maisel et al. J Am Coll Cardiol. 2013;62(2):150–160.

18.  Möckel M et al. Eur J Emerg Med. 2013;20:103–108. DOI: 10.1097/MEJ.0b013e328351e609.

19.  Gu YL et al. Clin Res Cardiol. 2011;100(12):1069–1076. DOI: 10.1007/s00392-011-0343-y.

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