By Martin Moeckel
Other authors: Prof. Dr. Evangelos Giannitsis, MD, PhD (Germany)Prof. Dr. Stefan Blankenberg, MD, PhD (Germany); Prof. Dr. Kurt Huber, MD, PhD (Austria); Prof. Dr. Christian Müller, MD, PhD (Switzerland); Dr. Julia Searle, MD, (Germany); Anna Slagman, VD (Germany); Dr. Jörn Ole Vollert, MD, MBA (Germany); Prof. Dr. Christian Hamm, MD, PhD (Germany)
Background / Purpose:
According to the Universal Definition of acute myocardial infarction (AMI), all patients with suspected ACS without ST elevations in the ECG require serial troponin testing (Thygesen 2012).
Copeptin, a stable fragment of pro-vasopressin is a marker for severe, hemodynamic stress and has been studied as a marker for the early rule-out of myocardial infarction in several observational trials with very promising results (Reichlin 2009, Keller 2010, Giannitsis 2011).
This is the first interventional trial to study whether it is safe to discharge patients who test troponin and copeptin negative at admission without further clinical and laboratory evaluation.
Patients with suspected ACS and a negative baseline troponin, who also test negative for copeptin at admission, can safely be discharged and will not experience a higher proportion of MACE within 30 days after their admission than patients who are managed by standard practice of care.
Multicenter, international, randomized, controlled clinical trial (RCT). Patients (n=892) are randomized 1:1 into standard and experimental arm (Figure 1). A telephone follow-up is performed at 30 and 90 days. The study complies with the declaration of Helsinki.
Troponin negative patients with a negative copeptin value at admission [cutoff 10pmol/L] are discharged into ambulant care. An outpatient visit is scheduled within 72hours to assure the patient’s well-being. Patients with a positive copeptin receive standard treatment according to current guidelines.
Patients are treated as by standard of care according to current guidelines. Copeptin values are not revealed to the treating staff.
The non-inferiority margin was previously defined as 5%. An intention to treat analysis (ITT) will be performed. If more than 10% of the patients did not receive the process they were assigned to, additional per protocol analyses will be performed.
This is the first interventional trial on the safety of copeptin-guided early rule-out of AMI in patients with suspected ACS. If the hypothesis is confirmed, a high proportion of patients could be discharged early, thus unnecessary treatments and resources could be saved, causing a substantial benefit for patients and health care providers.
The authors are congratulated on having performed an important and well performed study. This kind of study – a randomized controlled trial comparing a new diagnostic strategy with the current standard strategy –is unfortunately uncommon, but precisely what is needed in the era of evidence based medicine.
The evaluated strategy is based on positive criteria for rapid rule-out1, which is opposite to the conventional concept of having only positive criteria for the diagnosis of AMI. By using a combination of cardiac Troponin (cTn) and Copeptin it was possible to discharge 66% of the patients directly from the ED compared to only 12% in the conventional arm; and that with a similar rate of the composite endpoint at 30-days, around 5.5 %, in both arms. This clearly illustrates the strength of a RCT; if we hadn’t been able to compare with the event rate in the conventional arm we would probably have considered the 5% event rate of the new strategy unacceptable.
There are some limitations of the study: the number of patients and events were limited, leading to fairly wide confidence intervals around the composite endpoint; and the number of patients lost to follow-up was somewhat high, 7%.
Some proposed alternative rule-out strategies also need to be evaluated in prospective trials: A single hs-cTn with a cut-off substantially below the 99th percentile level 2, two measurements of hs-cTn 1 hour apart 3 and the combination of hs-cTn and a risk score 4.
The concept of having a specific rule-out strategy in addition to a more conventional rule-in strategy does have the possibility to change clinical practice.
1. Lindahl B, Venge P, Wallentin L. Early diagnosis and exclusion of acute myocardial infarction by biochemical monitoring. Coronary Artery Disease. 1995;6: 321-8.
2. Rubini Giménez M, Hoeller R, Reichlin T, et al. Rapid rule out of acute myocardial infarction using undetectable levels of high-sensitivity cardiac troponin. International journal of cardiology. 2013 [Epub ahead of print]doi:pii: S0167-5273(13)01103-0. 10.1016/j.ijcard.2013.06.049.
3. Reichlin T, Schindler C, Drexler B, et al. One-hour rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin t. Archives of Internal Medicine. 2012;172:1211-1218
4. Melki D, Jernberg T. Heart score: A simple and useful tool that may lower the proportion of chest pain patients who are admitted. Crit Pathw Cardiol. 2013;12:127-131.