FAQ

A1. How safe is the Copeptin + Troponin concept to rapidly rule out acute myocardial infarction (AMI) in low-to-intermediate-risk patients?

In low-to-intermediate-risk patients, the Copeptin + Troponin rapid AMI rule-out concept demonstrated very high safety in the recently- completed, multicenter, multinational prospective, randomized, controlled interventional Biomarkers in Cardiology-8 (BIC-8) study^Ref-1, described as “seminal” in a recent European Heart Journal editorial^Ref-2. Additionally, the concept has shown very high negative predictive values (NPVs), that is, rates of correct rule-out, in numerous prospective observational studies.

• For example, a recent meta-analysis^Ref-3 of 14 prospective observational studies involving 9,244 patients in total found the Copeptin + Troponin strategy had very high sensitivity and NPV to correctly rule out AMI (90.5% sensitivity, 97.0% NPV). This NPV represented a significant improvement over that of Troponin alone (P <0.001).
• In BIC-8^Ref-1, the Copeptin + Troponin strategy preserved safety, achieving the study’s pre-specified primary endpoint of non- inferior safety to that of the conventional process. The 30-day major cardiovascular adverse event (MACE) rate (link to the following text “The BIC-8 study defined major cardiovascular adverse events as any of death from any cause, survived sudden cardiac arrest, rehospitalization for acute coronary syndrome (ACS) acute unplanned percutaneous coronary intervention (PCI) coronary artery bypass grafting (CABG) documented life-threatening arrhythmias.”)
• by intention-to-treat analysis was low and virtually indistinguishable in the Copeptin + Troponin group versus the conventional process (serial Tn testing) group: 5.19% vs. 5.17%. Indeed, by per-protocol analysis, the Copeptin + Troponin had a numerically lower 30-day MACE rate: 3.01% vs. 5.34%. Moreover, unlike the conventional process group, in the Copeptin group there were no cases of death.

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).

Thus, for example, the BIC-8 protocol reflected good medical practice in considering biomarkers within the patient’s complete clinical context. The protocol even included a final clinical assessment before any discharge. Based on clinical judgment, the BIC-8 treating physicians could delay discharge and/or admit for further evaluation patients who were initially Copeptin-negative and Troponin-negative. They did so uncommonly, i.e., in <20% of Copeptin-negative/Troponin-negative patients (further evaluation recommended in 72/367). Moreover, for patients discharged from the ED because of rapid AMI rule-out using Copeptin plus Troponin, the BIC-8 protocol included an outpatient cardiologist appointment within 72 hours, and preferably 48 hours, of discharge.

A2. How effective is the Copeptin + Troponin concept to rapidly rule out acute myocardial infarction (AMI)?

The best, and very robust, published data on the efficacy of the Copeptin + Troponin rapid AMI rule-out concept come from the recently-completed, multicenter, multinational Biomarkers in Cardiology-8 (BIC-8) study^Ref-1 of low-to-intermediate-risk patients (GRACE score ≤140) with suspected AMI. This study is noteworthy for its prospective, randomized, controlled, interventional design, and indeed, was named “seminal” in a recent article in the European Heart Journal^Ref-2.

In BIC-8, 67.6% of patients in the Copeptin + Troponin study arm were discharged from the emergency department (ED), without need for protracted monitoring there or in the chest pain unit (CPU). That rate was a 5.6-fold higher than the 12.0% ED discharge rate seen in the conventional process study arm. 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, other protracted monitoring and several electrocardiography (ECG). The difference between arms in the rate of ED discharge was statistically significant (P < 0.001).

A3. In what proportion of patients can acute myocardial infarction (AMI) be correctly ruled out with the combination of single Copeptin and Troponin measurements at presentation?

Data from large prospective observational studies as well as the recently-completed multicenter, multinational, prospective, randomized, controlled, interventional Biomarkers in Cardiology-8 (BIC-8) study^Ref-1 suggest that this combination correctly rules out acute myocardial infarction (AMI) in the vast majority of patients. For example, a recent meta-analysis^Ref-3 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 that with Troponin alone (P < 0.001).

A4. In what proportion of patients can acute myocardial infarction (AMI) be correctly ruled out with the combination of single Copeptin and Troponin measurements at presentation?

Data from large prospective observational studies as well as the recently-completed multicenter, multinational, prospective, randomized, controlled, interventional Biomarkers in Cardiology-8 (BIC-8) study^Ref-1 suggest that this combination correctly rules out acute myocardial infarction (AMI) in the vast majority of patients. For example, a recent meta-analysis^Ref-3 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 that with Troponin alone (P < 0.001).

A5. Why would cardiologists benefit from a marker for early rule-out of acute myocardial infarction (AMI)?

Whether a cardiologist, an emergency physician, or a physician of another specialty, any clinician who assesses patients with symptoms suspicious for AMI in an acute setting should benefit from a marker that assists in safe, rapid rule-out of that condition. At least in theory, such rule-out should

• allow physicians to more rapidly direct appropriate treatment and monitoring towards their patients
• relieve overcrowding caused by patients undergoing unnecessary protracted monitoring for possible AMI. ED overcrowding has been significantly linked to:
  1. delayed intravenous thrombolysis in patients with suspected AMI^Ref-4
  2. decreased adherence to guideline–recommended therapies and higher risk of recurrent MI in patients with non-ST-segment elevation myocardial infarction (NSTEMI)^Ref-5
  3. more frequent death or adverse cardiovascular outcomes (AMI, heart failure, hypotension, dysrhythmias, or cardiac arrest not seen at presentation, but occurring during an inpatient stay) in patients hospitalized for chest pain or related possibly cardiac complaints^Ref-6
  4. increased mortality at 2 days^Ref-7 7 days^{Ref-7, 8} and 30 days^Ref-7
• in general, allow physicians to deploy healthcare resources more efficiently.

A6. What is a negative predictive value (NPV)?

The negative predictive value, or NPV, is the proportion of patients with negative test results who are correctly classified, i.e., correctly identified as not having the disease (true negatives/all negatives). The NPV depends not only on the quality, i.e., sensitivity and specificity of the test, but also on the prevalence of the disease.

B1. What does a high (or positive) Copeptin value mean? What is the impact on the differential diagnosis?

In the setting of suspicion of acute myocardial infarction (AMI), an elevated Copeptin value means that this condition CANNOT be ruled out. An elevated Copeptin value with a simultaneous negative Troponin value indicates serial Troponin measurement. Clinicians of course should bear in mind 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).

B2. What do the following Copeptin/Troponin value combinations mean?

Troponin+/Copeptin+: The probability of acute myocardial infarction (AMI) is high. The Copeptin elevation suggests that the AMI occurred within the previous 10 hours.

Troponin+/Copeptin-: The probability of AMI is high. The low Copeptin value may mean that the AMI possibly occurred >10 hours before. Of course, the high Troponin value may also reflect a medical condition other than AMI, e.g., heart failure, sepsis, pulmonary embolism, or atrial fibrillation; nevertheless, as a first step, the possibility of AMI would need to be investigated further.

Troponin-/Copeptin+: The negative Troponin value may indicate that AMI occurred too recently for damaged cardiomyocytes to release sufficient Troponin into the circulation to produce a positive Troponin value, i.e., that the patient is in the “Troponin-blind period.” The Copeptin elevation may be attributable to AMI, since Copeptin, as a marker of severe hemodynamic stress, typically rises very rapidly after AMI.
The Troponin-/Copeptin+ value combination therefore indicates a need for a repeat Troponin measurement after at least 3 hours when using hs-Troponin or from 6 to 9 hours with the conventional Troponin^Ref-9. If the repeat Troponin value turns out to be positive, AMI is highly probable. AMI also is highly probable if there is a change in Troponin levels between measurements that exceeds the institutional cut-off.
Moreover, there are other diseases that may lead to a positive Copeptin value without a subsequent Troponin elevation^Ref-10.

Troponin-/Copeptin-: AMI is highly unlikely and low-to-intermediate- risk patients typically can be safely discharged after a final clinical assessment if nothing else in the clinical picture contraindicates doing so. For example, in the multicenter, multinational, prospective, randomized, controlled, interventional Biomarkers in Cardiology-8 study (BIC-8)^Ref-1, 67.6% of patients (305/451) in the Copeptin group were discharged from the emergency department, with an outpatient cardiologist appointment within 72 hours, and preferably 48 hours; remaining patients were assigned to further evaluation because of their overall clinical picture. This increased discharge rate in the Copeptin arm was achieved while preserving safety: by both intention- to-treat and per-protocol analyses and in all 4 sensitivity analyses, the Copeptin arm achieved the pre-specified primary endpoint of non- inferior safety to that of the conventional process. Moreover, unlike the conventional process group, in the Copeptin group there were no cases of death.

B3. What should the Copeptin cut-off value be when the Copeptin/Troponin strategy is used to rapidly rule out acute myocardial infarction (AMI)?

In the Biomarkers in Cardiology-8 (BIC-8) multinational, multicenter, randomized, controlled clinical process study evaluating safe, early emergency room discharge using single Troponin and copeptin measurements at presentation in patients with suspected acute coronary syndrome (ACS), a copeptin cut-off at 10 pmol/L was recommended to rule out AMI. In this study, a Copeptin value of ≥10 pmol/L or above was considered to be positive. However, each institution is of course free to determine its own Copeptin cut-offs for rapid rule-out of AMI through analyzing its own data and consulting the literature.

B4. Does Copeptin rise during an acute myocardial infarction (AMI) even without chest pain?

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 probably stimulated by endogenous stress, and is not related to the sensation of physical pain.

B5. In healthy volunteers, median Copeptin values are higher in men than in women. Is gender a potential confounding factor when interpreting Copeptin values for the rapid rule-out of acute myocardial infarction (AMI)?

Copeptin values appear not to differ significantly between men versus women with a diagnosis of AMI, as suggested by published analyses of the datasets from two observational studies ^{Ref-11, 12}. Median Copeptin values in healthy men and women were reported to be 5.2 pmol/L and 3.7 pmol/L, respectively^Ref-13, while a Copeptin cut-off of 10 pmol/L was used in the multinational, multicenter, prospective, randomized, controlled interventional Biomarkers in Cardiology-8 (BIC-8) study^Ref-1 of Copeptin + Troponin in rapid rule-out of AMI. One may speculate that Copeptin secretion stimulated by the severe hemodynamic stress associated with an AMI overwhelms the gender difference seen in healthy people.

B6. How does alcoholic beverage ingestion or cigarette smoking affect Copeptin levels?

Literature regarding the effects of alcohol^Ref-14 or nicotine or cigarette smoking^Ref-15-17 on vasopressin, 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 are those related to acute myocardial infarction (AMI), and therefore would be expected to seldom if ever confound interpretation of Copeptin results in AMI rule-out.

C1. Can all patients with a negative Copeptin value be directly sent home?

The results of the recently-completed multicenter, multinational Biomarkers in Cardiology-8 (BIC-8) prospective, randomized, controlled, interventional study^Ref-1 as well as of a variety of earlier prospective observational studies^{,e.g. Ref-11, 12, 18, 19,} suggest that low-to- intermediate-risk (GRACE score ≤140) patients with negative Copeptin AND negative Troponin at presentation typically may be safely discharged from the emergency department – if warranted by the comprehensive clinical assessment. As with values of any biomarker or biomarker combination, Copeptin and Troponin values should never be used in isolation to guide patient management – the entire clinical picture must be considered.
A negative / negative combination of the two biomarkers does not necessarily mean that a patient can be sent home, but it means that is possible to discharge patients with a high probability of not having a myocardial infarction.
In BIC-8, for instance, 67.6% of patients (305/451) in the study’s “Copeptin arm” were discharged from the emergency department, with an outpatient cardiologist appointment within 72 hours, and preferably 48 hours. Based on the comprehensive context, including clinical assessment, treating physicians assigned about 20% of Copeptin-negative and Troponin-negative patients (72/367) for further evaluation.

C2. When/why is a 2nd Troponin measurement unnecessary if Copeptin as well as Troponin are used for rapid rule-out of acute myocardial infarction (AMI)?

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 before circulating levels rise above the cut- off for positivity. This up to 6 hours between AMI onset and Troponin positivity is the so-called 'Troponin-blind' period (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.

D1. What is BIC-8 and why is it so important?

BIC-8, which stands for Biomarkers in Cardiology-8^Ref-1, was a recently- completed prospective, multicenter, multinational process study described as “seminal” in a recent European Heart Journal editorial^Ref-2. The study was notable for four reasons. First, BIC-8 was randomized and controlled, giving its findings strength and robustness in the era of evidence-based medicine. Second, BIC-8 was an interventional study, meaning that patient management was guided by the diagnostic strategies that the study assessed. Therefore BIC-8 could determine those strategies’ effects on actual patient outcomes. Third, BIC-8 was the first randomized, controlled, interventional study to demonstrate that rapid rule-out of acute myocardial infarction (AMI) using single measurements of Troponin and Copeptin at presentation allowed a significantly greater proportion of low-to-intermediate-risk patients to be discharged from the emergency department, without repeat Troponin testing or protracted monitoring – and with preserved safety. Fourth, BIC-8 is a process study that has determined a change in the framework of the chest pain assessment.

D2. Where did BIC-8 take place, who was the principal investigator, what was its study design, and where were the data reported?

The Biomarkers in Cardiology-8 study, BIC-8, took place in 7 sites at 6 centers in 3 European countries: the Hamburg University Heart Center, Heidelberg University Clinic, the Kerckhoff Clinic in Bad Nauheim, and two sites of the Charité Hospital, Berlin, in Germany; Wilhelminenthospital, Vienna, in Austria; and the Basel University Hospital in Switzerland. The BIC-8 principal investigator was Prof. Dr. Martin Möckel of Charité University Hospital, Berlin.

The BIC-8 study design is summarized in Figure A6. Patients were randomized 1:1 to either of two study arms: the “Copeptin arm” (the experimental arm) or the “conventional process arm.” In both arms, patients received the study center’s state-of-the-art diagnostic testing and monitoring, including Troponin testing. In the Copeptin arm, however, patients underwent Copeptin testing at presentation and their physicians were made aware of the Copeptin values. Most notably, in the Copeptin arm, patients were discharged from the emergency department if both Copeptin and Troponin at presentation were negative, and if there was no contraindication for doing so. Thus in the Copeptin arm, patients with negative initial Copeptin and Troponin typically avoided further Troponin testing and more protracted monitoring and evaluation in the emergency department or chest pain unit. Instead, discharged patients were given an outpatient cardiologist appointment for within 72 hours, and preferably, 48 hours of presentation.

As a result of the early AM rule-out using initial Copeptin + Troponin measurements, the BIC-8 Copeptin arm had a significantly greater emergency department discharge rate than did the “conventional process” (serial Troponin measurement) arm: 67.6% vs. 12.0%, P <0.001. Besides this 5.6-fold higher emergency department discharge rate, the Copeptin arm had significantly decreased median length-of-stay – by 3 hours – overall and in the subgroup in the hospital ≤1 day, i.e., in the emergency department or chest-pain unit. Median length-of-stay was 4 hr vs. 7 hr overall and 4 hr vs. 7 hr in patients in the hospital ≤1 day (P <0.001, both comparisons).

BIC-8 results were reported in a “Hot Line Session” devoted to noteworthy new data from clinical studies, held on 3 September 2013 at the European Society of Cardiology Annual Congress in Amsterdam, The Netherlands. The initial BIC-8 manuscript now has been published and can be downloaded at no charge from eurheartj oxfordjournals.org

E1. Copeptin and other blood biomarkers in AMI rule-out

Highly-sensitive Troponin assays may decrease the length of the “Troponin-blind period” (Troponin diagnostic gap). However, experts still are sufficiently concerned about that period that the most recent European Society of Cardiology treatment guidelines speak of a second Troponin test after at least 3 hours when Troponin is the only blood biomarker used to rule out AMI^Ref-9. This requirement typically would entail the patient waiting, and undergoing monitoring, in the emergency department (ED), chest pain center (CPU), or other acute care facility, i.e., a ≥3-hour delay in discharge for patients in whom AMI rule-out is based on two Troponin measurements. The combination of Copeptin and Troponin entails a new “Touch and Solve” framework of the chest pain assessment, which is safe and effective.

Of interest, highly-sensitive Troponin assays were used in clinical routine – and hence, as per the protocol, used in the trial – exclusively in 4/7 sites and partially in 2/7 sites in the recently-completed, multicenter, multinational prospective, randomized, controlled, interventional Biomarkers in Cardiology-8 (BIC-8) study^Ref-1. Notwithstanding the wide application of state-of-the-art Troponin assays, in BIC-8, use of a combination of initial Copeptin and initial Troponin measurements allowed a 5.6-fold higher rate of direct discharge home than did use of serial Troponin measurement without Copeptin data: 67.6% in the Copeptin arm vs. 12.0% in the conventional process arm (P < 0.001).

Also of interest, a collaborative meta-analysis^Ref-3 using data from altogether 4692 patients from 9 observational studies found that adding an initial Copeptin determination to an initial highly-sensitive Troponin measurement significantly improved negative predictive value, i.e., the rate of correct rule-out, compared to use of highly-sensitive Troponin testing alone: the negative predictive value (95% confidence interval) rose from 96.2% (95.4%–96.8%) with highly-sensitive Troponin alone to 98.2% (97.5%–98.7%) with Copeptin as well as highly-sensitive Troponin.

E2. Aren’t there other biomarkers besides Copeptin, e.g., CK / CK-MB, myoglobin or heart fatty acid binding protein (HFABP), that can be used together with Troponin for rapid rule-out of acute myocardial infarction (AMI)?

No biomarker besides Copeptin has yet been shown by a prospective, randomized, controlled, interventional study to safely, rapidly rule out AMI when a single measurement is used in conjunction with a contemporaneous single Troponin determination. The combination of single Copeptin/Troponin measurements at patient presentation was reported to provide safe, effective rapid AMI rule-out in low-to- intermediate-risk patients (GRACE score < 140) in the recently- completed multicenter, multinational, prospective, randomized, controlled, interventional Biomarkers in Cardiology-8 (BIC-8) study^Ref-1. The novelty and quality of BIC-8 has led to the study being described as “seminal” in a recent European Heart Journal editorial^Ref-2.

Since myoglobin and CK/CK-MB reflect the same pathophysiological mechanism as Troponin (cell damage due to necrotic tissue or cardiac injury), adding one of these markers to Troponin provides no valuable additional information. Copeptin release due to the endogenous stress, on the other hand, reflects a different pathophysiological process and therefore provides additional information to that provided by the necrosis marker Troponin.