Article, Cardiology

Necessity of hospitalization and stress testing in low risk chest pain patients

a b s t r a c t

Background: Copeptin is a marker of endogenous stress including early myocardial infarction(MI) and has value in early rule out of MI when used with cardiac troponin I(cTnI).

Objectives: The goal of this study was to demonstrate that patients with a normal electrocardiogram and cTnIb 0.040 ug/l and copeptinb 14 pmol/l at presentation and after 2 h may be candidates for early discharge with outpatient follow-up potentially including stress testing.

Methods: This study uses data from the CHOPIN trial which enrolled 2071 patients with acute chest pain. Of those, 475 patients with normal electrocardiogram and normal cTnI(b 0.040 ug/l) and copeptinb 14 pmol/l at presenta- tion and after 2 h were considered “low risk” and selected for further analysis.

Results: None of the 475 “low risk” patients were diagnosed with MI during the 180 day follow-up period (includ- ing presentation). The negative predictive value of this strategy was 100% (95% confidence interval(CI):99.2%- 100.0%). Furthermore no one died during follow up. 287 (60.4%) patients in the low risk group were hospitalized. In the “low risk” group, the only difference in outcomes (MI, death, revascularization, cardiac rehospitalization) was those hospitalized underwent revascularization more often (6.3%[95%CI:3.8%-9.7%] versus 0.5%[95%CI:0.0%-

Abbreviations: CAD, coronary artery disease; Cardrehosp, cardiac rehospitalization events; CI, confidence interval; cTnI, cardiac troponin I; “Low risk” group, denotes those with normal electrocardiogram and normal troponin I (b0.040 ug/l) and copeptin (b 14 pmol/l) at presentation and 2 h; MI, myocardial infarction.

* Corresponding author at: P.O. Box 3080, Laguna Hills, CA 92654, United States.

E-mail address: [email protected] (N. Beri).

0735-6757/(C) 2016

2.9%], p = .002). The hospitalized patients were tested significantly more via stress testing or angiogram (68.6%[95%CI:62.9%-74.0%] vs 22.9%[95%CI:17.1%-29.6%], p b .001). Those tested had less cardiac rehospitalizations during follow-up (1.7% vs 5.1%, p = .040).

Conclusions: In conclusion, patients with a normal electrocardiogram, troponin and copeptin at presentation and after 2 h are at low risk for MI and death over 180 days. These low risk patients may be candidates for early out- patient testing and cardiology follow-up thereby reducing hospitalization.

(C) 2016

  1. Introduction

Chest pain is one of the most common presenting symptoms to the emergency department (ED), accounting for 9-10% of visits, which equates to 5.5 million visits a year [1]. One multicenter study estimated that approximately 55% of patients with chest pain are ultimately ad- mitted [2] for monitoring and further testing but under 13% are ulti- mately diagnosed with acute coronary syndrome [1]. Studies estimate the average cost per hospital day to be as high as $4293 [3,4]. Further- more, in a 2012 study of Medicare patients, chest pain was the most common reason for short inpatient stays, representing 22.5%, more than the next six reasons combined [5]. During this period, patients are typically monitored clinically and via serial cardiac markers; they often undergo inpatient stress testing while some proceed directly to coronary angiography. Recently, there has been significant interest in early discharge of Low risk chest pain patients recognizing the high cost of hospitalization.

Arginine vasopressin is a neurohormone secreted by the posterior pituitary during times of significant stress, including cardiovascular stress [6]. Copeptin is the stable c-terminal part of the vasopressin pro-hormone used as a surrogate for measurement of vasopressin, which has a very short half-life and thus can be difficult to measure [7]. Copeptin has been shown to be elevated early in acute coronary syn- drome [8], and it can facilitate early, safe rule out of acute myocardial in- farction (MI) in conjunction with troponin [9-15]. Most recently, Mockel et al., completed a study suggesting that a single troponin and copeptin at admission in low to intermediate risk patients with Suspected acute coronary syndrome is non-inferior for early rule-out of MI versus the current standard process of serial monitoring of cardiac markers [10]. Currently, many of these low to intermediate patients risk are admitted for stress testing. One study examined the effect of inpa- tient stress testing and found that although it reduced readmissions,

such a strategy was not cost-effective [16].

In the multi-center Copeptin Helps in the Early Detection of Patients with Acute Myocardial Infarction (CHOPIN) trial, “low risk” was defined using a single Blood draw strategy of normal troponin and copeptin at presentation alone. In this study, we examine a more stringent “low risk” sub-cohort of patients with normal copeptin and troponin I (as well as electrocardiogram) at presentation and 2 h within the CHOPIN trial to determine the rate of adverse cardiac events, subsequent test uti- lization, and intervention. We sought to demonstrate the low risk na- ture of this group, making the patients candidates for discharge from the Emergency Department and outpatient follow up rather than hospi- tal admission.

  1. Methods
    1. Study Design and Population

This is a retrospective analysis of data from the Copeptin Helps in the Early Detection of Patients with Acute Myocardial Infarction (CHOPIN) trial, a 16-center prospective study of 2071 patients who presented with non-traumatic chest pain within 6 h of symptom onset. Patients were included in the CHOPIN study if they were over 18 years of age and the ED physician had any suspicion of acute coronary syndrome. Local laboratory values guidED patient care. In addition, blood draws

were performed at presentation, 2 h, 6 h, and 24 h if the patient was still hospitalized. The blood was centrifuged and stored at -60 ?C or below and sent to a core laboratory for analysis. Follow-up was conduct- ed via phone and review of medical records at 30, 90, and 180 days. In- stitutional review board approval was received at all 16 sites in the CHOPIN trial, and all patients provided written consent. The CHOPIN trial was conducted in compliance with International Conference on Harmonization and Good Clinical Practice regulations.

First, to demonstrate the value of copeptin, in this study, out of 2071 patients with chest pain, we selected 644 patients with normal electro- cardiogram and troponin I (b 0.040 ug/l) at presentation and 2 h and fur- ther subdivided this group into those with normal copeptin (b 14 pmol/l) and elevated copeptin (Fig. 1). Outcomes at 180 days (in- cluding presentation) were analyzed.

Having demonstrated the value of copeptin, for this study, we de- fined a “low risk” cohort of patients as those 475 patients with a normal electrocardiogram (including absence of ST segment changes and T wave inversions), cardiac troponin I (cTnI, from core laboratory) under 0.040 ug/l at presentation and after 2 h and copeptin under 14 pmol/l at presentation and after 2 h (Fig. 2). This low risk cohort was evaluated for cardiac events (including MI, death, revascularization, cardiac rehospitalization) at presentation and in the future.

Final Diagnosis

Two board-certified cardiologists blinded to copeptin data indepen- dently determined the patient’s final diagnosis based on serial troponins (from the core laboratory) and chart review. Diagnoses were assigned to one of six categories: 1) ST-elevation myocardial infarction, 2) non-ST

Fig. 1. Additional value of copeptin 644 patients with normal EKG and troponin and presentation and 2 h (out of 2071 patients with acute chest pain) were analyzed to show the additional value of copeptin. They were divided into a group that had normal copeptin (defined as copeptin under 14 pmol/l) at presentation and 2 h, which comprised 475 “low risk” patients and 169 patients with elevated copeptin.

Fig. 2. Study design Patient distribution according to initial electrocardiogram, cTnI (cutoff 99th percentile; 0.040 ug/l) at presentation and 2 h, and copeptin (cutoff 14 pmol/l) at presentation and 2 h. The “low risk” 475 patients were then subdivided into hospitalized and discharged groups and sub-divided into tested and nontested groups. “Tested” denotes patients that underwent stress testing or angiogram. For a final diagnosis of acute MI, patients either positive cTnI or copeptin are assumed to undergo a second cTnI measurement. Card rehosp = cardiac rehospitalization events.

elevation MI, 3) unstable angina, 4) cardiovascular disease but not acute coronary syndrome, 5) noncardiac chest pain, and 6) unclassified cause of chest pain. The endpoints committee reviewed all final diagnoses.

Biomarker Assays

Cardiac troponin I was measured locally and at the core labo- ratory. The core Laboratory analysis was performed using a cTnI Ultra assay on an ADVIA Centaur XP system (Siemens Healthcare Diagnostics, Norwood, MA). Per the manufacturer, the detection range was 0.006 ug/l to 50 ug/l with 99th percentile of 0.040 ug/l and 10% coefficient of vari- ation of 0.030 ug/l. A troponin cut-off of 0.040 ug/l was used for this study.

Copeptin was measured using an EDTA plasma sample analyzed at the core laboratory on a Kryptor Compact platform (BRAHMS GmbH (now part of Thermo Fisher), Henningsdorf, Germany). According to the manufacturer, the assay detection range was 4.8 to 500 pmol/l, up to 1200 pmol/l with automatic dilution with functional sensitivity (low- est value with interassay coefficient variation under 20%) of b 12.0 pmol/l. The myocardial infarction rule-out cutoff used was 14 pmol/l as in the CHOPIN trial, based on a review of the literature [8, 9,11,13].

Study End Points

The primary endpoint of this study was MI and death from presenta- tion to 180 days. Secondary endpoints of the study included cardiac re- hospitalization, and revascularization.

Statistical Analysis

Statistical analysis was performed using SPSS version 21. Normally distributed continuous variables are described using means and standard deviations. Non-normal continuous distributions are described by the median and interquartile range. Categorical variables are expressed as proportions in the form of percentages. For continuous variables, Student’s t-test or Mann-Whitney were used as appropriate (for normal distributions or non-normal distributions, respectively). Confidence inter- vals were calculated as 95% two-sided intervals using the exact method. For categorical variables, chi square testing was used. The data manage- ment center and the statistician at the Veteran Affairs San Diego were in- volved in Data quality control and statistical analysis.

  1. Results
    1. Additional Value of Copeptin

To demonstrate the value of copeptin, 644 patients with normal EKG and normal troponin (b 0.040 ug/l) at presentation and at 2 h were se- lected out of 2071 patients with chest pain (Fig. 1). This group was di- vided into a group with normal copeptin (b 14 pmol/l) at presentation and 2 h and one with elevated copeptin at either time point. The group with normal copeptin had 475 patients and the group with ele- vated copeptin had 169 patients. Outcomes over the next 180 days (in- cluding presentation) were analyzed (Table 1) as a goal of this study is to identify chest pain patients who are safe enough to be discharged.

As seen in Table 1, copeptin added value to three of the four analyzed endpoints. The 180 day MI rate was significantly lower in the group with normal copeptin (0.0% vs 3.0%, p b .001). The 180 day Death rate was also significantly lower in the normal copeptin group (0.0% vs 1.2%, p = .02). Further, the 180 day cardiac rehospitalization rate was significantly lower in the normal copeptin group (3.4% vs 7.1%, p =

.04). The revascularization rate at 180 days was also lower in the normal copeptin group (4.0% vs 5.3%, p = .47) although the difference was not statistically significant.

Taken together, these data suggest that copeptin adds value in iden-

tifying chest pain patients at overall lower cardiac risk over 180 days in- cluding presentation.

Having demonstrated the value of copeptin, the 475 “low risk” pa- tients discussed above were included in this study (Fig. 2). The low risk cohort was defined as the patients with a normal electrocardiogram and normal troponin I (b 0.040 ug/l) and copeptin (b 14 pmol/l) at pre- sentation and after 2 h.


In this low risk cohort, 188 patients (39.6%) were discharged from the ED while 287 (60.4%) were hospitalized. In terms of demographics, hospitalized low risk patients were, on average, older and were more likely to have a history of revascularization, known CAD, and hyperlip- idemia (Table 2). They also had a slightly higher systolic blood pressure which was statistically but not clinically significant. There was no differ- ence in copeptin levels between groups. However, there was a minor difference in troponin levels as the hospitalized group was more likely to have detectable troponin (but still under 0.040 ug/l). The difference was so small that the median and interquartile range of troponin appear to be the same for the hospitalized and discharged groups in Table 2.

Immediate Events

In terms of events at presentation, no patients (0.0% [95% CI: 0.0%- 0.8%]) were diagnosed with MI and none (0.0% [95% CI: 0.0%-0.8%]) died in the ED or within 30 days of presentation. In terms of interven- tions, 15 patients (3.2% [95% CI: 1.8%-5.2%]) were revascularized during the initial presentation, including 12 (2.5% [95% CI: 1.3%-4.4%]) who re- ceived percutaneous coronary intervention with stent placement and 3 (0.6% [95% CI: 0.1%-1.8%]) who had Coronary artery bypass grafting per- formed. Only one intervention was considered urgent by the inpatient team.

180 Day Events (Including Presentation)

During the 180 day follow-up, no patients experienced MI (0.0% [95% CI: 0.0%-0.8%]) and none died (0.0% [95% CI: 0.0%-0.8%]) (Fig. 3).

The negative predictive value for MI of normal electrocardiogram and normal troponin I/copeptin at presentation and 2 h was 100% (95% CI: 99.2%-100.0%) for this study (Table 3). There were 19 (4.0% [95% CI: 2.4%-6.2%]) revascularization events, including percutaneous coronary intervention and coronary artery bypass during this period. There were 16 patients (3.4% [95% CI: 1.9%-5.4%]) who were rehospitalized for cardiac reasons. Thus, the relatively low risk of the “low-risk”

(normal electrocardiogram/troponin I/copeptin) group extends to MI and All-cause death at 180 days as well as revascularization and cardiac rehospitalization.

Ischemic Testing and Revascularization by Group

In terms of evaluation for obstructive CAD, over half of patients (240 patients, 50.5%) underwent testing with either exercise treadmill test- ing, stress imaging, or coronary angiogram during the 180 day follow- up (Fig. 4). This resulted in 19 (4.0% [95% CI: 2.4%-6.2%]) revasculariza- tion events.

Hospitalized Versus Discharged in Low RiskGroup

Comparing the hospitalized and discharged cohorts, the hospitalized patients (n = 287; 60.4%) underwent significantly more testing (via stress testing and angiography) and interventions than the discharged group (Table 4). In the hospitalized group, 197 (68.6% [95% CI: 62.9%- 74.0%]) had either a stress test or coronary angiography, including 45 (15.7% [95% CI: 11.7%-20.4%]) who went directly to angiography and 17 (5.9% [95% CI: 3.5%-9.3%]) who went to angiography after a stress test. In contrast, in the discharged group, only 43 (22.9% [95% CI: 17.1%-29.6%], p b .001) underwent testing, including 4 (2.1% [95% CI: 0.5%-5.4%], p b .001) who went straight to angiography. None of the discharged patients (0.0% [95% CI: 0.0%-1.9%], p = .001) underwent an- giography after stress testing. In the hospitalized group, 15 (5.2% [95% CI: 2.9%-8.5%]) underwent revascularization during the initial presenta- tion versus 0 (0.0% [95%CI: 0.0%-1.9%], p = .001) in the discharged group. Three (1.1% [95% CI: 0.2%-3.0%]) patients in the hospitalized group were later revascularized at 180 days (excluding presentation) versus one (0.5% [95% CI: 0.0%-2.9%], p = .55) in the discharged group, a difference that was not statistically significant. The cardiac re- hospitalization rate at 180 days was not significantly different (3.5% ver- sus 3.2%, p = .86) in the two groups and there were no deaths or MIs in either group. Thus, the only major difference between the hospitalized and discharged subgroups of the “low-risk” cohort was that the hospi- talized group was tested and subsequently revascularized more fre- quently. The more extensive testing may partially account for the difference in revascularization rate.

Tested Versus Non-tested Groups

The tested and non-tested groups were also compared and evaluat- ed for differences in outcomes during the 180 day follow-up period. In the group of 240 patients tested for CAD, 4 (1.7%) were rehospitalized for cardiac reasons while in the non-tested group of 235 patients, 12 (5.1%, p = .040) were rehospitalized for cardiac reasons (Fig. 5). The tested patients were more likely to have detectable troponins (p =

.046). Interestingly, although those hospitalized were significantly more likely to be tested and those tested were significantly less likely to have a cardiac rehospitalization, hospitalization itself had no relation- ship with cardiac rehospitalization (3.5% vs 3.2%, p = .86).

Table 1

Additional value of copeptin in normal ekg and normal troponin (presentation & 2 h) group.

Event rates (including presentation)

Normal copeptin group (N = 475)

Elevated copeptin group (N = 169)


180 day MI rate




180 day death rate




180 day revascularization rate




180 day cardiac rehospitalization




Notes: 644 patients with normal EKG and troponin and presentation and 2 h (out of 2071 patients with acute chest pain) were analyzed to show the additional value of copeptin. They were divided into a group that had normal copeptin (defined as copeptin under 14 pmol/l) at presentation and 2 h, which comprised 475 “low risk” patients and 169 patients with elevated copeptin.

Table 2

Baseline characteristics.

Baseline characteristics (with percentages) – normal electrocardiogram/troponin/copeptin

N valid

All “low risk” (n = 475)

Hospitalized (n = 287)

Discharged (n = 188)



Age (mean +- SD)


52.2 +- 11.4

53.7 +- 10.7

49.9 +- 12.0




247 (52.0%)

154 (53.7%)

93 (49.5%)


cardiac risk factors/comorbidities

History of MI


72 (15.3%)

51 (17.8%)

21 (11.2%)




82 (17.5%)

61 (21.3%)

21 (11.2%)


Known CAD


101 (21.6%)

75 (26.1%)

26 (13.8%)


Family history of CAD


188 (46.4%)

112 (39.0%)

76 (40.4%)




84 (17.8%)

53 (18.5%)

31 (16.5%)


peripheral artery disease


14 (3.0%)

7 (2.4%)

7 (3.7%)




27 (5.7%)

11 (3.8%)

16 (8.5%)




217 (47.3%)

147 (51.2%)

70 (37.2%)




261 (55.2%)

163 (56.8%)

98 (52.1%)


Chronic Kidney disease


2 (0.4%)

1 (0.3%)

1 (0.5%)


Heart failure


15 (3.2%)

8 (2.8%)

7 (3.7%)


Atrial fibrillation


19 (4.1%)

9 (3.1%)

10 (5.3%)


Smoker (current)


122 (25.7%)

69 (24.0%)

53 (28.2%)


Smoker (ever)


253 (53.3%)

159 (55.4%)

94 (50.0%)


Cardiac arrest


4 (0.8%)

2 (0.7%)

2 (1.1%)


Ventricular tachycardia


6 (1.3%)

5 (1.7%)

1 (0.5%)


Vitals and labs

Heart rate


79.9 +- 15.3

79.5 +- 15.0

80.5 +- 15.6


Systolic blood pressure (mm Hg)


141.6 +- 23.7

143.6 +- 24.9

138.4 +- 21.5


Diastoic blood pressure (mm Hg)


80.9 +- 13.7

81.4 +- 14.1

80.0 +- 13.2


Respiratory rate (per minute)


17.9 +- 2.2

17.8 +- 2.3

18.0 +- 2.2


Body mass index (kg/m2)


31.0 +- 8.1

30.5 +- 7.6

31.8 +- 9.0


Creatinine (mg/dl) (median


0.9 [0.7-1.0]

0.9 [0.7-1.0]

0.8 [0.7-1.0]


[interquartile range])

Hemoglobin (g/dl) (median


13.7 [12.8-14.8]

13.9 [12.9-14.9]

13.6 [12.7-14.6]


[interquartile range])

Biomarker (median [interquartile range])

Copeptin (pmol/l) at


5.6 [0-8.6]

5.7 [0-8.8]

5.3 [0-8.1]



cTnI (ug/l) at presentation


0 [0-0.006]

0 [0-0.006]

0 [0-0.006]


Copeptin (pmol/l) at 2 h


5.5 [0-8.3]

5.3 [0-8.2]

5.9 [0-8.8]


cTnI (ug/l) at 2 h


0 [0-0.006]

0 [0-0.006]

0 [0-0.006]


Notes: Values are means +- standard deviation, median [25%-75% percentile], or n (%) and compared with Student t-test, Mann-Whitney test, or the Pearson chi-square test (categorical variables). Actual total number by diagnostic subgroup may be lower for variables with missing data. The value 0 represents undetectable levels of copeptin and cTnI, respectively.

CAD = coronary artery disease; cTnI = cardiac troponin I, MI = myocardial infarction.

  1. Discussion

In this study, we found “low risk” patients defined as a normal elec- trocardiogram at presentation and a normal copeptin and troponin I at presentation and after 2 h had an extremely low risk of death and MI at 180 days, thus meeting the primary endpoint of the study. Further- more, these patients had a low risk for revascularization, and cardiac re- hospitalization. Thus, we have identified a cohort of patients that are

candidates for rapid assessment and discharge with outpatient follow up. It further shows that stress testing and medical management of these patients is associated with a lower rate of cardiac rehospitaliza- tion. It is the first study to evaluate the Need for hospitalization and ex- amine the utility of stress testing in this low risk population.

Currently, patients are ruled out for myocardial infarction using con- ventional troponin. A major limitation of conventional troponin Is the delayed rise in the event of an MI, which has traditionally led to serial

Fig. 3. Total 180 day events for the low risk group Total 180 day events in low risk group including events on presentation. 95% exact confidence intervals are also shown. There were no MIs and no one died during the 180 day follow up in the low risk group.

Table 3

Prediction of MI at 180 days for the low risk group.

Electrocardiogram/troponin/copeptin for prediction of MI at 180 days (including presentation)

Table 4

Testing and interventions.

Testing in the hospitalized versus discharged subgroups of the “low risk” cohort

Hospitalized Discharged

Sensitivity 100% [98.1%-100.0%]

Specificity 25.3% [23.3%-27.3%]

Negative predictive value 100% [99.2%-100.0%]

Positive predictive value 12.1% [10.5%-13.8%]

Negative likelihood ratio 0.0

Percent tested or intervened upon

“Low risk” group (n = 475) n = 287

Percent tested or intervened upon

n = 188


Notes: Sensitivity, specificity, negative and positive predictive value as well as negative



likelihood ratio are shown for the “low risk” selection criteria of normal electrocardiogram

Any testing



b 0.001

and normal troponin and copeptin at presentation and 2 h. The 95% exact confidence in-

Stress test



b 0.001

terval is also provided in brackets.

Stress test then angiography




Angiography without stress testing



b 0.001

Revascularized in hospital




sampling over several hours. There has been much interest recently in shortening the rule-out time for MIs. One proposed method, which has been validated by several studies, utilizes copeptin which is elevat- ed early during the course of an MI [6-15]. Once a patient has been ruled out for MI, the decisions of hospitalization versus discharge and wheth- er further testing is necessary must be made. Short to medium term prognosis plays a major role in this decision.

Secondary endpoints of the study were to confirm the low risk na- ture of the normal electrocardiogram, normal troponin/copeptin group both at presentation and at 180 day follow up not only with regards to MI and all-cause mortality but also cardiac rehospitalization, and revascularization. The “low risk” group met these endpoints. Fur- ther, the only major difference between the hospitalized and discharged group was the amount of testing and revascularization. We found that stress testing was associated with reduced rates of cardiac rehospitali- zation. One prior study examined the effect of inpatient stress testing and found that it reduced readmissions but was not cost-effective [16]. Thus, from a cost-efficacy standpoint, stress testing would ideally be done in the Outpatient setting.(if felt to be clinically appropriate) given the extremely low risk of MI and death in this population.

The low rate of death and MI at 180 days suggests that management of these patients may reasonably take place in the outpatient setting. Our finding that these low risk chest pain patients may be candidates for early discharge and follow up dovetails nicely with current American Heart Association and American College of Cardiology guide- lines which state as a class IIa recommendation that “it is reasonable for patients with possible ACS [acute coronary syndrome] who have normal serial electrocardiograms and cardiac troponins to have a treadmill elec- trocardiogram, stress myocardial perfusion imaging, or stress echocar- diography before discharge or within 72 hours after discharge” [17]. Given that no MI’s or deaths occurred over 180 days in this population, it is possible that a time window of more than 72 h may be reasonable for possible stress testing, but further studies would be needed to

Fig. 4. Revascularization in the low risk group Revascularization events are shown. N refers to the subgroup in the “low risk” group who underwent testing; note that for “revascularization”, N was assumed to be the total low risk group.

Revascularized at 180 days (excluding





Cardiac rehospitalization at 180 days




Notes: Testing and interventions are shown for the low risk group subdivided into hospi- talized and discharged cohorts. “Any testing” indicates either stress test or angiogram.

make this determination. Further, outpatient follow up may also allow for better clarification of the patient’s symptoms. Not uncommonly, there are instances in which the patient cannot or would be unlikely to follow up. In these instances in particular, depending on Patient symptoms, admission for further testing may be appropriate. Of course, there are always individual circumstances and ultimately, the overall clinical picture (which may not be adequately reflected in studies) should be taken into account.

Limitations with the study include that it was retrospective and did not include high sensitivity troponins (as they were not available in the database) which are increasingly studied for early rule-out of MI [18]. It is possible that future events were prevented by revascularization or medical management of some patients in the “low risk” hospitalized group; however, it is likely that the discharged cohort had some signif- icant coronary artery disease, which went undetected and yet they had no events at 180 day follow up. Overall, the results do not suggest that hospitalization and early ischemic testing significantly reduces future MIs, although it may be that the benefits would not be apparent outside of a very large, randomized trial as these patients are already Very low risk for MI over a period of 6 months.

In the future, prospective, randomized large-scale studies may fur- ther develop the concept of early discharge and management of patients

Fig. 5. Rehospitalization in tested and non-tested groups Survival curve in the tested and nontested groups in the low risk group of 475 patients. Here, the x-axis represents days to either death or cardiac rehospitalization. As there were no deaths in the group at 180 days, this effectively represents days to cardiac rehospitalization.

similar to those in this cohort. Future studies may also directly compare strategies using copeptin versus high sensitivity troponin for identifica- tion of a population of patients who may be candidates for early discharge.

  1. Conclusion

In conclusion, we found that the combination of a normal electrocar- diogram at presentation with a normal troponin I and copeptin at pre- sentation and after 2 h defines a truly low risk population for MI or death at 180 days. This cohort may be candidates for early outpatient testing and follow-up if it can be arranged in a timely manner, thereby reducing hospitalization. Our data also suggests that early stress testing may reduce the rate of cardiac rehospitalization; this would ideally be done in the outpatient setting given the substantial costs associated with hospital admission. The strategies outlined might assist with pa- tient disposition and management in the emergency department and the outpatient setting and reduce overall treatment costs. Future re- search should prospectively evaluate the management of these low risk chest pain patients including the role for stress testing in this group and examine the effect on overall treatment cost.


Dr. Neil Beri: none.


This study uses data from the CHOPIN trial. BRAHMS AG (now part of ThermoFisher) supported the CHOPIN trial but did not provide funds for this study. They had no role in this study.


We would like to acknowledge the UCSD Biomarker Research Center.


  1. Bhuiya FA, Pitts SR, McCaig LF. Emergency department visits for chest pain and ab- dominal pain: United States. NCHS Data Brief 1999-2008;2010:1-8.
  2. Lindsell CJ, Anantharaman V, Diercks D, Han JH, Hoekstra JW, Hollander JE, et al. The In- ternet Tracking Registry of Acute Coronary Syndromes (i*trACS): a multicenter registry

of patients with suspicion of acute coronary syndromes reported using the standardized reporting guidelines for emergency department chest pain studies. Ann Emerg Med 2006;48:666-77 677.e1-9. doi:10.1016/j.annemergmed.2006.08.005.

  1. 2013 Comparative Price Report: Variation in medical and hospital prices by country. Int Fed Heal Plans 2014 ( 534fc9ebe4b05a88e5fbab70/1397737963288/2013+iFHP+FINAL+4+14+14.

pdf accessed May 8, 2016).

  1. Rappleye E. Average cost per inpatient day across 50 states. Becker’s Hosp Rev 2015 ( across-50-states.html accessed May 8, 2016).
  2. Memorandum Report. Hospitals’ use of observation stays and short inpatient stays for Medicare beneficiaries, OEI-02-12-00040; 2013.
  3. Mueller C. Biomarkers and acute coronary syndromes: an update. Eur Heart J 2014; 35:552-6.
  4. Bolignano D, Cabassi A, Fiaccadori E, Ghigo E, Pasquali R, Peracino A, et al. Copeptin (CTproAVP), a new tool for understanding the role of vasopressin in pathophysiolo- gy. Clin Chem Lab Med 2014;52:1447-56.
  5. Keller T, Tzikas S, Zeller T, Czyz E, Lillpopp L, Ojeda FM, et al. Copeptin improves early diagnosis of acute myocardial infarction. J Am Coll Cardiol 2010;55:2096-106.
  6. Maisel A, Mueller C, Neath S-X, Christenson RH, Morgenthaler NG, McCord J, et al. Copeptin helps in the early detection of patients with acute myocardial infarction: primary results of the CHOPIN trial (Copeptin Helps in the early detection Of Pa- tients with acute myocardial INfarction). J Am Coll Cardiol 2013;62:150-60.
  7. Mockel M, Searle J, Hamm C, Slagman A, Blankenberg S, Huber K, et al. Early dis- charge using single cardiac troponin and copeptin testing in patients with suspected acute coronary syndrome (ACS): a randomized, controlled Clinical process study. Eur Heart J 2015;36:369-76.
  8. Reichlin T, Hochholzer W, Stelzig C, Laule K, Freidank H, Morgenthaler NG, et al. In- cremental value of copeptin for rapid rule out of acute myocardial infarction. J Am Coll Cardiol 2009;54:60-8.
  9. Lipinski MJ, Escarcega RO, D’Ascenzo F, Magalhaes MA, Baker NC, Torguson R, et al. A systematic review and collaborative meta-analysis to determine the incremental value of copeptin for rapid rule-out of acute myocardial infarction. Am J Cardiol 2014;113:1581-91.
  10. Sebbane M, Lefebvre S, Kuster N, Jreige R, Jacques E, Badiou S, et al. Early rule out of acute myocardial infarction in ED patients: value of combined high-sensitivity cardi- ac troponin T and ultrasensitive copeptin assays at admission. Am J Emerg Med 2013;31:1302-8.
  11. Raskovalova T, Twerenbold R, Collinson PO, Keller T, Bouvaist H, Folli C, et al. Diag- nostic accuracy of combined cardiac troponin and copeptin assessment for early rule-out of myocardial infarction: a systematic review and meta-analysis. Eur Hear J Acute Cardiovasc Care 2014;3:18-27.
  12. Jayasinghe R, Narasimhan S, Tran TH, Paskaranandavadivel A. Rapid rule out of myo- cardial infarction with the use of copeptin as a biomarker for cardiac injury. Intern Med J 2014;44:921-4.
  13. Mallidi J, Penumetsa S, Friderici JL, Saab F, Rothberg MB. The effect of inpatient stress testing on subsequent emergency department visits, readmissions, and costs; 2013. J Hosp Med 8:564-8.
  14. Amsterdam EA, Wenger NK, Brindis RG, Casey DE, Ganiats TG, Holmes DR, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes; 2014. J Am Coll Cardiol 64:e139-228. 1016/j.jacc.2014.09.017.
  15. Bandstein N, Ljung R, Johansson M, Holzmann MJ. Undetectable high-sensitivity car- diac troponin T level in the emergency department and risk of myocardial infarction; 2014. J Am Coll Cardiol 63:2569-78.

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