Introduction

Background

Patients with chest pain and a prehospital electrocardiogram with ST-segment elevation myocardial infarction (STEMI) are preferably treated with heparin, aspirin and a P2Y12 inhibitor by the ambulance personnel and transported to the nearest percutaneous coronary intervention (PCI) centre for immediate reperfusion therapy [1–4]. However, in a number of patients, symptoms and ST-segment shifts completely resolve before initiation of the PCI procedure, and optimal management of this situation is not outlined in the current guidelines. The incidence of patients with such a transient STEMI, or TSTEMI as it is referred to [5], is estimated to be between 4–18 % [5, 6], though often not reported. It can be postulated that prehospital treatment and the use of newer antiplatelet agents with faster bioavailability will increase this number even further. The optimal management of this syndrome has not yet been established. The current practice of treating patients with TSTEMI varies between physicians and hospitals. Often logistical factors like time of the day and availability of the catheterization laboratory play an important part in the decision-making. Presently, there are no randomized controlled trials addressing the topic of optimal timing of coronary angiography and subsequent revascularisation in patients with TSTEMI.

In patients with persistent ST-segment elevation, primary PCI without further delay is the preferred reperfusion strategy [3, 4]. The optimal timing of intervention in patients presenting with acute coronary syndromes without ST-segment elevation (NSTE-ACS) has been debated for years. The ABOARD trial included patients with NSTE-ACS and compared a strategy of immediate intervention (mean time to start of intervention 70 min) with a strategy of intervention deferred to the next working day (mean time 21 h) and showed no difference in infarct size as defined by peak troponin level [7]. The TIMACS trial revealed a significant 38 % reduction in death, myocardial infarction (MI) or stroke at 6 months in high-risk NSTE-ACS patients (GRACE score >140), with an early (≤24 h) compared with a delayed (≥36 h) strategy. No significant difference in treatment strategy was observed in patients with a low to intermediate risk profile (GRACE score ≤140) [8]. Furthermore, a recent analysis showed no relation between the timing of angiography and long-term cardiovascular mortality or MI in NSTE-ACS patients [9]. Only a minority of patients in these trials had a TSTEMI, but the proportion is not reported; hence, no further conclusions can be drawn from these results.

Meisel et al. described 69 consecutive patients with TSTEMI and compared them with a conventionally treated matched control group with persistent ST-segment elevation. Patients with TSTEMI had coronary angiography 36 ± 39 h after symptom onset, showing TIMI 2–3 flow in the majority (84 versus 38 % in the STEMI group). The TSTEMI patient group had less myocardial damage, less extensive coronary artery disease and a better cardiac function as measured with echocardiography [5]. This might suggest that optimal medical therapy with a delayed invasive approach is an appropriate therapy in patients presenting with TSTEMI. Meneveau et al. investigated a matched comparison between a group of 39 patients with TSTEMI treated with immediate angioplasty, and a group of 39 patients with TSTEMI treated with delayed angioplasty (24 h) [10]. All patients had a thrombus-containing lesion. Patients in the delayed group showed thrombus load reduction at the time of PCI and less procedural-related complications, suggesting superiority of a delayed strategy compared to an immediate invasive approach.

Both current European and American guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation recommend an early invasive strategy (within 24 h) for high-risk patients (GRACE score >140) and a delayed invasive strategy for intermediate risk patients (GRACE score ≤140) [11, 12]. No recommendations are provided for patients with TSTEMI. Transient ST-segment elevation suggests an area of transmural ischaemia and might identify a high-risk patient that may benefit from immediate intervention by preventing on-going ischaemia or reinfarction. On the other hand, the above-mentioned observations suggest that these patients have better outcome than STEMI patients, and a delayed invasive approach may prevent procedural related myocardial infarction and therefore even be superior to immediate intervention [5, 10]. The present study aims to provide data on whether a STEMI-like approach with immediate invasive therapy or a non-STEMI-like approach with optimal pharmacological pretreatment is the most appropriate in this particular patient cohort.

Study Objectives

The primary objective is to evaluate whether a delayed invasive strategy is superior to an immediate invasive strategy, in patients presenting with a TSTEMI by reducing infarct size measured with cardiovascular magnetic resonance (CMR). The secondary objectives will assess the need for urgent revascularisation, left ventricular function and volumes, myocardial salvage and microvascular injury at baseline; the change in left ventricular function, volumes and infarct size at 4 months; and major adverse cardiac events (MACE) at 4 and 12 months.

Methods

Overview

The TRANSIENT Trial is a prospective, multicentre, investigator initiated randomized controlled trial of an immediate versus a delayed invasive strategy in patients with a TSTEMI. Patients are eligible for the study if they have a clinical presentation of an acute STEMI including chest pain and ST-segment elevations on the prehospital electrocardiogram of at least 2 mm in two standard limb leads or in two contiguous chest leads and subsequently complete resolution of electrocardiographic changes and symptoms with or without initial treatment of sublingual nitrate, heparin, P2Y12 inhibitor and/or aspirin. Further inclusion and exclusion criteria are listed in Tables 1 and 2. A total of 142 patients will be randomly assigned to an immediate or delayed invasive strategy (ratio 1:1). A flow chart of the study design is shown in Fig. 1. All randomized patients will be included in an intention-to-treat analysis.

Table 1 Inclusion criteria transient trial
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Table 2 Exclusion criteria transient trial
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Fig. 1
figure 1

Study flow chart Transient Trial. (STEMI, ST-segment elevation myocardial infarction)

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Patient Enrolment

The study protocol conforms to the international Conference on Harmonization/Good Clinical Practice standards. Participating hospitals have submitted the protocol for approval by the local ethics committee. Patients with a TSTEMI will be randomized, after informed consent is obtained, upon arrival in the hospital to either the immediate or delayed coronary angiography group. The randomization will be a permuted-block randomization, stratified according to study centre.

All patients will be treated medically with aspirin, a P2Y12 inhibitor, a beta blocker, nitroglycerin, a statin and heparin. Dual antiplatelet therapy will be continued for 1 year according to current guidelines. Patients will further receive all other standard medical treatment for an acute coronary syndrome at the discretion of the treating physician and according to the guidelines.

Coronary Angiography and Revascularisation

Patients will undergo coronary angiography and revascularisation immediately, or delayed and pending on the GRACE score (>140 within 24 h or ≤140 within 72 h). If patients in the delayed group show signs of coronary reocclusion while waiting for their intervention, they will undergo urgent intervention and reported as event.

Thrombus burden will be assessed using the Thrombolysis in Myocardial Infarction (TIMI) thrombus grading scale. The flow indices to be determined are the Myocardial Blushing Grade (MBG) and the Thrombolysis in Myocardial Infarction (TIMI) flow grade both before and after PCI.

PCI will be performed according to standard procedures and left to the discretion of the operator. In case of intermediate stenosis, a fractional flow reserve (FFR) measurement will guide in the decision-making. In case of multivessel disease, the strategy will be based on the SYNTAX score and local Heart Team protocol.

Cardiovascular Magnetic Resonance

The baseline CMR scan will be scheduled at 3–5 days after the start of chest pain, and follow-up will be performed at 4 months (Fig. 2). Patients are studied on a clinical 1.5 or 3.0 Tesla scanner using a phased array cardiac receiver coil. All images are ECG-gated and acquired during mild end-expiration breath-holding. For functional imaging, cine steady-state free precession images are obtained during repeated breath-holds in the three standard long axis views (four-, three- and two-chamber view). Contiguous short axis slices are acquired covering the entire left ventricle from base to apex, to examine regional and global left ventricular function. Precontrast T1 and T2 mapping and postcontrast T1 mapping will be performed at the level of the infarcted area, for calculation of T1-relaxation and T2*-decay measurements [13, 14]. Late gadolinium-enhanced (LGE) images are acquired 10 min after administration of a gadolinium-based contrast agent with an inversion-recovery gradient-echo pulse sequence, to identify the size and extent of myocardial infarction as previously described [15]. All data are obtained with identical slice locations for comparison of the different sequences. All CMR images are sent to a core laboratory for quality control and blinded central analysis.

Fig. 2
figure 2

Example of cardiovascular magnetic resonance images 4 days (a–f) and 4 months (g–j) after transient inferior acute myocardial infarction, demonstrating the acquisitions to determine the different end points. a Diastolic and b systolic cine image to determine cardiac function, volumes and mass; c T2 imaging and d T2* mapping visualizes acute injury through high signal intensities (arrows) compared to remote myocardium; precontrast and e postcontrast T1 mapping determines the tissue content of infarcted myocardium; f late gadolinium enhancement for assessment of infarct size and extent (hyperenhanced, green-dotted area) and area at risk (white-dotted area) using the endocardial surface area (red line) [16]. g Diastolic and h systolic cine image to calculate the change in cardiac function after 4 months; i T2 imaging to exclude recent acute injury; j late gadolinium enhancement to calculate the regression in infarct size after 4 months (green area)

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From the recorded CMR images, left ventricular volumes are measured and ejection fraction is calculated using the summation of slice method multiplied by slice distance. Regional T1-relaxation and T2*-decay times will be determined in the infarcted and remote myocardium, and the LGE images will be used to measure infarct size and extent. Furthermore, the LGE images will be used to assess the presence and extent of microvascular injury (central dark zones within the hyperenhanced, infarcted myocardium) and to measure the area at risk using the endocardial surface area method [16]. Since both cine and LGE image acquisitions are performed using identical slice positions within one imaging session, both data sets are matched per slice, to combine functional and LGE information per segment. Comparison of follow-up to baseline images is achieved by consensus of two observers using anatomic landmarks.

Blood Sampling

Venous blood samples for CK, CK-MB mass and troponin T determination will be obtained at admission and at 3, 6, 12, 24, 36, 48 and 72 h in the immediate group. In the deferred group, this will be performed at the same time points, and additionally at 3, 6, 12, 24, 36 and 48 h after coronary angiography and subsequent revascularisation. At admission, directly prior to PCI and at 4 months follow-up, c-reactive protein and the coagulation status of the patients will be assessed. Prothrombin fragment F1 + 2, a cleavage product that is released during activation of prothrombin to thrombin and d-dimer, degradation product of fibrin, will be analyzed by ELISAs to provide information on the in vivo procoagulant state. Von Willebrand factor will be used as marker for the activation state of endothelial cells, and will be determined by ELISA. Finally, in vitro thrombin generation will be tested with calibrated automated thrombography. This test analyzes the in vitro capacity of plasma to form thrombin under standardized conditions.

Major Bleeding

Major bleeding is defined using the TIMI criteria as the need for transfusion of >2 units of whole blood or packed red blood cell, intracranial or retroperitoneal haemorrhage, a fall in haemoglobin of 2.5 mmol/L (or 12 % of haematocrit) without an identifiable bleeding site, spontaneous or non-spontaneous blood loss associated with 2 mmol/L decline of haemoglobin (or 10 % of haematocrit) and vascular surgery for bleeding complications [17].

Major Adverse Cardiac Events

MACE is defined as cardiac death, target vessel revascularisation or MI and is evaluated at 4 and 12 months after the index hospitalization. The occurrence of myocardial infarction is evaluated using both the WHO [18] and SCAI criteria [19].

Outcomes

The primary objective of the study is total infarct size as percentage of the left ventricle at baseline CMR scan, performed 4 days after the start of symptoms. Secondary outcomes include the following: area at risk, myocardial salvage and microvascular injury at baseline and infarct size at 4 months measured by CMR; the need for urgent revascularisation during follow-up; the difference in infarct size measured by troponin T and CK MB as area under the curve; the occurrence of recurrent ischaemia requiring urgent revascularisation; the occurrence of major bleeding during the index hospitalization defined by the TIMI bleeding criteria and MACE at 4 and 12 months (see also Table 3).

Table 3 Secondary end points assessed at 4 and 12 months follow-up
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Sample Size Considerations

The study is powered for the primary endpoint of difference in infarct size between the two treatment groups at baseline, measured by LGE CMR. In a previous study in patients after acute MI treated by primary PCI, we have demonstrated a mean infarct size of 17 % of the left ventricle with CMR, with a standard deviation of 10 % [15]. In NSTEMI patients, these results are lower, e.g. Xu et al. [20] reported a mean infarct size of 10 % of the left ventricle with a standard deviation of 5 %. It is assumed that patients with normalized ST-segment ACS are more likely to show CMR characteristics similar to NSTE-ACS patients as compared to STEMI patients. We hypothesize that there will be a 25 % reduction in infarct size in the delayed treatment group (a reduction in infarct size from 10 to 7.5 % of the left ventricle). It is desired to have a power of 80 % to detect a difference in infarct size between the two treatment groups, assuming a standard deviation of 5 %. Therefore, with 64 patients in each group, the study has 80 % power to detect a 2.5 % difference (with α = 0.05) between early and delayed intervention. Based on the experience in previous studies, it is assumed that up to 10 % of patients will be unavailable with respect to the infarct size measurements. The sample size must be correspondingly increased to compensate for this loss of information. To maintain 80 % power, an increase to a total of 142 patients is required.

Discussion

Both current European and American guidelines on the treatment of patients with NSTE-ACS advise an invasive strategy pending on risk stratification [11, 12]. In patients with NSTE-ACS and a high risk (defined as a GRACE score >140), there is a reduction in the composite of death, MI or stroke with an early (within 24 h) invasive strategy. This benefit is not seen in patients with a low to intermediate risk (GRACE score ≤140) [8]. The cohort of patients suspected of NSTE-ACS is divers, ranging from pulmonary, gastrointestinal, musculoskeletal or psychiatric cause, to non-ischaemic cardiovascular origin (i.e. aortic dissection, myocarditis, pericarditis) or ischaemic atherosclerotic diagnosis [21] and can also consist of patients with TSTEMI. The diagnostic workup at the emergency department will further stratify patients for additional testing to define the right diagnosis. Patients with TSTEMI, on the other hand, frequently have a clear presentation with distinct ST-segment deviation and typical symptoms, which fully resolve after initial medical treatment and at admission to the hospital. An immediate invasive procedure to ensure myocardial perfusion seems obvious, but since perfusion has been restored, a more careful and patient-based approach may be more desirable to enhance plaque or thrombus stabilization and reduce reperfusion injury through embolization of thrombus content [10].

In the era of primary PCI as the preferred treatment for patients with STEMI, a substantial part of patients have reperfusion during the initial angiography and before primary PCI is performed. These patients have resolved symptoms and may presumably have electrocardiographically normalization of the ST-segment and should be classified as TSTEMI. Stone et al. reported on the results of four PAMI primary PCI trials and showed spontaneous reperfusion (TIMI 3 flow) in 16 % of patients at initial angiography [22]. These patients are less likely to develop complications related to left ventricular failure and have improved early and late survival. Analogue to STEMI patients, TSTEMI patients may benefit from an immediate invasive procedure by preventing cardiovascular events (reinfarction) that could potentially occur while waiting for a delayed intervention and in doing so reduce infarct size. As mentioned before, a delayed approach may actually be preferable, allowing stabilization of the patient and time for the ruptured plaque to heal and thrombus load to reduce. In the OPTIMA trial, for example, immediate PCI was associated with an increased rate of MI in comparison with a 24–48 h deferred strategy in patients with a NSTE-ACS [23].

From previous trials investigating NSTE-ACS patients or patients with STEMI and TIMI 3 flow during primary intervention, it is known that mortality is low; and therefore, a large number of patients have to be included to have sufficient power to detect a difference in clinical endpoints between therapeutic strategies. Therefore, the surrogate end point infarct size has been chosen in this study to detect differences between treatment arms. Infarct size is known to be closely related to morbidity and mortality and strongly predicts patient outcome after coronary interventions [24, 25]. CMR using a gadolinium-based contrast agent is an established method for infarct size calculation in both acute and chronic MI [26, 27] and is currently considered the gold standard. Besides infarct size, it offers an accurate and reproducible measure of cardiac function [28]. The more recent improvements in CMR, such as T1 and T2 mapping, offer techniques to further delineate subtle changes in the myocardium caused by mechanical reperfusion and recognized predictors of outcome (i.e. infarct-related edema, reperfusion-induced microvascular injury and haemorrhage) [13, 29, 30], which is especially important when evaluating the optimum timing of reperfusion and comparing the potential complications of each strategy.

The answer to the key question of the optimal timing of revascularisation in patients with TSTEMI remains unclear and has not previously been addressed in an adequately powered, randomized controlled trial with well-defined end points. After completion of this trial, we anticipate to complement the guidelines for all patients with acute ST-segment elevation myocardial infarction, including TSTEMI.