In this prospective observational study, copeptin in combination with high sensitivity troponin T at admission had a higher sensitivity to identify ACS than hsTnT alone and the use of the combination at admission was found to be equivalent to, or better than, a renewed hsTnT after 3-4 hours. In the NSTEMI subgroup the sensitivity was as high as 98% with a NPV of 99% and this finding is in line with several other studies [5, 6, 12, 14, 16, 17].
Fewer studies have focused on the entire ACS population. Keller et al.  reported a NPV of 80% in the ACS population when combining a 4th generation troponin T test and copeptin. In a relatively small study (n = 58) with high proportion ACS  it was reported a sensitivity of 87% and a NPV of 83% when combining hsTnT and copeptin at admission and this was comparable to a second hsTnT sample after 3 hours. These results are similar to our findings.
Although the sensitivity is significantly increased, it is important to note that the NPV increases only slightly, by a few percentages, and this finding is also consistent with other studies [6, 10, 11, 13–15]. In our study of 478 patients, the combination of hsTnT and copeptin decreased the number of false negative tests by 15 as compared to hsTnT alone. This was at a cost of 74 more false positives. Since our study population consisted of only admitted patients and the intention was to identify patients who may be discharged early, we argue that decreasing the amount of false negatives is of importance to maintain an appropriate level of safety.
Overall it seems as if copeptin, a marker of endogenous stress, adds diagnostic information in ACS and that the combination of copeptin and hsTnT is equivalent to, or better than, a second hsTnT value measured 3-4 hours after admission. In the ESC guidelines a rapid rule out of AMI with a second hsTnT after 3 hours is suggested . Our results indicate that hsTnT and copeptin analysed at admission, with a NPV of 99%, can be used to rule out AMI with a very high accuracy, and thus makes a second hsTnT unnecessary.
A clinical problem is the UAP patients, where 24 out of 37 patients in our material were hsTnT- negative at admission. Our study is the first larger study using the combination of hsTnT and copeptin addressing this issue. Reichlin et al.  report no significant difference in copeptin concentration between UAP patients and patients with other diagnosis than ACS and attributes this to that UAP does not cause sufficient endogenous stress for vasopressin release. In our material (Table 5), although not statistically significant, the trend was that copeptin values are higher in the UAP patients compared to the non-ACS group, and the addition of copeptin detects 9 of the 24 hsTnT-negative UAP patients. Similar effects when adding copeptin have been reported by other authors [6, 13].
If rule out had been based on the combination of hsTnT and copeptin alone, 18 (3 NSTEMI and 15 UAP) out of 107 patients with ACS would have been misdiagnosed as non-ACS. In other words, 9% of the patients who were hsTnT and copeptin negative had a significant stenosis when undergoing a coronary angiography. Most will probably agree that this is too many and we come to the conclusion that biomarkers alone are not sufficient to rule out all ACS. Post-hoc we note that 9 of these patients were identified with stress testing, 7 based on history and ECG alone and 2 due to increasing hsTnT values. As suggested in current guidelines  we conclude that history, physical examination, ECG and further evaluation with risk stratification, rule-out of differential diagnosis and possible stress testing is needed. The missed ACS were mainly UAP with negative troponin during the hospital stay. Several previous studies have shown that troponin negative ACS have much better prognosis compared to troponin positive and may not be in need of immediate admission . It could be argued that they could be discharged to later evaluation in the out-patient clinic. For the high-risk group of troponin positive (NSTEMI) patients the NPV at admission was excellent (99%) for the combination missing only 1% of the NSTEMI patients. Since our results indicate that we achieve the same, or better, diagnostic accuracy with the combination of hsTnT and copeptin at admission than with a repeated hsTnT test, we suggest that clinical decisions regarding further investigations (according to guidelines) should be made already in the emergency department, saving at least 3 hours of observation.
Copeptin has also been suggested to be an independent powerful prognostic factor in patients with known coronary artery disease presenting with chest pain . We found that the prognosis was good during 60 days follow-up, with a low frequency of complications and no deaths (Table 2), in the group with negative hsTnT and copeptin. Maybe the combination of hsTnT and copeptin can be used to determine level of care, and allow early discharge in patients without remaining symptoms, with planned follow-up including a stress test when appropriate. This could in our material prevent more than 40% of the admissions of patients presenting with chest pain. It must, however, be kept in mind that the good prognosis may in part be due to that all patients with ACS in this group were intervened during the hospital stay. Further studies where patients are randomized to admission or discharge with follow-up are needed to answer this question, and these studies should also include patients with UAP.
Firstly, this is a single-center study. However, as our baseline characteristics are comparable to other studies including consecutive patients presenting with chest pain [4–6], we consider our results representative for unselected patient cohorts presenting with chest pain.
Secondly, we have no data on chest pain onset and as previously shown; copeptin is of greatest value early after onset, with an immediate rise, a peak value within 3 hours and a return to baseline in approximately 12 hours [6, 9]. The clinical value of copeptin may therefore be greater in early presenters. The pharmacokinetics might also, in patients with low peak values and delay from chest pain onset to blood sampling, cause false negative results. However, in these patients we expect that troponin has had time to rise above the cut off value and in this way the analyses supplement each other.
Thirdly, this is a prospective observational study and therefore we cannot measure the clinical effects of a more sensitive detection of ACS. Intervention studies are needed to provide this important additional information.