CORonary Thrombus Modification to Prevent MIcrovascular Damage in Patients With ST-segment Elevation Myocardial Infarction (The CORMI Trial)

Background: ST-elevation segment myocardial infarction (STEMI) most often occurs when an atherosclerotic plaque ruptures, causing blockage of the epicardial coronary artery leading to transmural ischemia of the myocardium. Due to ongoing ischemia, rapid restoration of blood flow with primary percutaneous coronary intervention (PCI) is vital to prevent further damage to the myocardium.

However, reopening of the coronary artery is by itself associated with damage to the myocardium, known as reperfusion injury. Reperfusion injury is a complex phenomenon mediated by several factors caused by the rapid restoration of blood flow. Oxidative stress, accumulation of intracellular calcium, rapid restoration of pH, and induction of inflammation are some of the underlying biological mechanisms.

Furthermore, the primary PCI procedure can cause distal embolization of the thrombus causing microvascular damage. In STEMI, coronary microcirculation plays a crucial role in myocardial reperfusion and recovery and cannot be visualizable by coronary angiography (CAG). The coronary microvascular dysfunction associated with primary PCI may lead to impaired myocardial reperfusion and worse outcomes. The increased microvascular damage occurs in part due to distal embolization of the thrombus and due to reperfusion injury to the ischemic area.

Coronary thrombus modification might lessen the distal embolization of the thrombus, by less abrupt changes to the thrombus, potentially reducing the damage associated with primary PCI with stent implantation. Ischemic post-conditioning is a coronary thrombus modification that has been introduced to alleviate the injury associated with reperfusion in patients with occluded coronary vessels. Ischemic post-conditioning can be achieved by briefly and repetitively blocking the culprit artery with a balloon inflated at a nominal size before completely reestablishing blood flow to the infarcted artery. The coronary thrombus modification achieved by ischemic post-conditioning could potentially lessen the distal embolization associated with primary PCI also in patient with partially reopened vessels by more slowly modifying the thrombus, and conditioning the damaged microcirculation to better tolerate ischemic damage if distal embolization occurs.

Using the index of microcirculatory resistance (IMR) and the novel microvascular resistance reserve (MRR) microvascular damage and dysfunction can be assessed invasively during primary PCI. Both MRR and IMR can be measured using the thermodilution method, which can be obtained either using continuous (only MRR) or bolus saline injection (MRR and IMR). Continuous thermodilution is obtained using the hyperemic effects of continuous infusion for saline, with minimal influence on hemodynamics, and have previously shown great reproducibility. Meanwhile, bolus thermodilution requires drug-induced hyperemia, usually obtained using intravenous adenosine, without the need for a specialized infusion catheter.

While coronary microvascular dysfunction in the setting of STEMI is an important predictor of clinical outcomes, most of the evidence is related to post-procedure measurements, which limits its ability in guiding treatment during the procedure. The data on pre-stenting measurements of microvascular damage is limited but could potentially serve as a tool in guiding treatment in future trials and more knowledge on the relationship of pre-stenting measurements and CMR outcomes is highly needed.

Even with rapid revascularization during STEMI, damage to the myocardium still occurs. The golden standard for assessing the degree of damage is cardiac magnetic resonance (CMR). The amount of myocardium perfused by the culprit vessels influences the degree of potentially salvageable myocardium by intervention, and the effects of treatment in patients with STEMI are usually evaluated by the amount of myocardium saved, called the myocardial salvage index (MSI), where lower MSI are associated with adverse outcomes following STEMI.

Methods: The study is a single-center randomized clinical trial in patients with STEMI referred for primary PCI. Patients will undergo physiological evaluation, with continuous and bolus thermodilution, after coronary flow has been achieved and prior to a 1:1 randomization between coronary thrombus modification or standard stent implantation. All patients will undergo PCI with stent implantation. At the end of the procedure, patients will undergo a repeat physiological evaluation with pressure and flow measurements, using both continuous and bolus thermodilution. Afterwards, the patients will undergo a CMR before discharge and within 7 days. Finally, CMR and invasive physiological evaluation will be repeated 3 months after the index procedure.

Using the electronic patient journal, clinical follow-up will be conducted in all included patients. Only information regarding death, myocardial infarction, any new revascularization and hospitalization for new or worsening heart failure will be collected. Clinical follow-up using the electronic patient journal will be conducted after 12 months, 24 months, and five years.

Statistics and sample size: Data is expected to be normally distributed, but normality will be tested using the Kolmogorov-Smirnov test or the Shapiro-Wilk test. Categorical data will be presented as numbers and frequencies, while Continuous data will be presented as means with standard deviations. Data will be compared using the Student´s t-test for continuous data, and Chi2-test for categorical data. When not normally distributed, data will be presented as medians with 25th and 75th quartile and compared using non-parametric tests. Associations will be evaluated using linear regression when data is continuous and using logarithmic regression when categorical. All analysis will be conducted as intention-to-treat.

An IMR ≥ 40, MRR ≤ 3, R(micro) > 500 CFR < 2, pre-stenting FFR ≤ 0.80 and post-stenting FFR < 0.90 will be considered abnormal. The optimal cut-off value of MRR and Rmicro is yet to be determined, why additional analysis will be conducted with an abnormal definition of MRR ≤ 2.5, R(micro) > 1000, and using the median of both values.

For the estimated sample size, data was based on the literature, where a previous study (Lønborg et. al. Ref number 1) found an IS/AAR of 51% ± 16 after ischemic post-conditioning and 63% ± 16 in the control group after 3 months. That study only enrolled patients with Thrombolysis In Myocardial Infarction (TIMI) flow 0-1 in the infarct related coronary artery.

As enrollment in the present study is not limited to TIMI 0-1 and MSI = 1-IS/AAR (and linear transformation preserves the SD), we estimated a MSI of 37% ± 16 in the control group and 47% ± 16 in the coronary thrombus modification group. With a two-sided alpha level of 0.05, 80% power, and a two-sample t-test, 42 patients are required in each group (84 total) to detect a statistically significant difference. To account for an anticipated loss to follow-up of 15%, a total of 100 patients is required.

Inclusion criteria

• ST-elevation at the J-junction in a minimum of two contiguous ECG leads with a minimum of ≥ 0.1 mV in all leads, except for V2 and V3 (which required ≥ 0.2 for men ≥ 40 years old, ≥ 0.25 in men < 40 years old, or ≥ 0.15 mV for all women) or new left bundle branch
• Admission to hospital within 12 hours of symptom debut
• Angiographic signs of a culprit lesion planned to be treated with primary percutaneous coronary intervention

Exclusion criteria

• Age < 18 years or inability to provide informed consent
• Life expectancy of < 12 months
• Hemodynamically instability
• Pregnancy or breastfeeding
• Known asthma or severe chronic obstructive pulmonary disease
• Expected inability to perform physiological measurements (due to severely tortuous arteries, ostial disease or very distal disease),
• CMR contraindications (estimated glomerular filtration rate < 30 mL/min, magnetic or mechanically activated implants, or any prior metal implants, severe claustrophobia)
• Expected to or unavoidable to use thrombectomy