Studies assessing the treatment of refractory no-reflow in patients with ST-elevation myocardial infarction (STEMI) are limited to clinical cases and pilot studies. This study aimed to evaluate the efficacy and safety of intracoronary adrenaline administration in such patients. Ninety consecutive patients with refractory coronary no-reflow during percutaneous coronary intervention (PCI) were prospectively included after the initial failure of conventional treatment. They were randomized into 2 groups: 45 patients in Group 1 received adrenaline, and 45 patients in Group 2 (control) received conventional treatments alone. After intracoronary drug administration, the adrenaline group demonstrated significantly higher rates of coronary flow restoration in the infarct-related artery to the level of thrombolysis in myocardial infarction grade 3 (56% vs 29% [p = 0.01]) and resolution of STEMI >50% after PCI (78% vs 36% [p <0.001]). Additionally, the adrenaline group showed a lower indexed microvascular obstruction (MVO) volume compared with the control group (0.9 [0.3; 3.1] % vs 1.9 [0.6; 7.9] % [p = 0.048]). A significant improvement in ejection fraction (EF) was observed in the adrenaline group (p = 0.025). Intracoronary adrenaline administration during PCI in patients with STEMI with refractory no-reflow is more effective compared with conventional treatments. This approach improves coronary flow in the infarct-related artery, facilitates a faster resolution of STEMI, enhances EF, and reduces MVO volume. Intracoronary adrenaline administration demonstrates a comparable safety profile to conventional treatment strategies in terms of life-threatening arrhythmias occurrence. The study suggests that intracoronary adrenaline administration during PCI could be an effective treatment strategy for patients with STEMI with refractory no-reflow.
Graphical-abstract
Over the past several decades, cardiology has focused on limiting ST-elevation myocardial infarction (STEMI) severity through early reperfusion therapies like thrombolytic therapy and percutaneous coronary intervention (PCI), significantly reducing mortality rates. , However, the benefits of early reperfusion are often compromised by microvascular obstruction (MVO). , Historically, diagnosing MVO, particularly the “no-reflow” phenomenon, was challenging, with limited sensitivity from the thrombolysis in myocardial infarction (TIMI) scale. The advent of contrast-enhanced cardiac magnetic resonance imaging (MRI) has improved MVO detection, revealing associations with larger infarct sizes and increased major adverse cardiac events (MACE). MVO has thus become a novel target for intervention in STEMI, , with predictive tools developed to anticipate no-reflow. , Despite advances, some cases remain refractory to conventional therapies. Microvascular arteriolar spasm, a reversible factor in no-reflow, suggests that coronary lytic drugs could be beneficial. Adrenaline, known for its coronary lytic effects, has shown promise in small-scale studies. , However, further validation of adrenaline’s efficacy on more sensitive reperfusion markers, such as MVO, is essential.
This study aimed to evaluate the effectiveness and safety of intracoronary adrenaline administration in refractory no-reflow phenomenon in patients with STEMI.
Methods
A single-center, prospective, controlled, interventional study titled “Efficiency and Safety of Intracoronary Epinephrine Administration in ST-Elevation Myocardial Infarction Patients with Refractory Coronary No-reflow” was conducted at the Cardiology Research Institute, a branch of the Tomsk National Medical Research Center. Informed consent for PCI was obtained upon hospital admission. In the event of the development of refractory no-reflow phenomenon, informed consent for participation in the study was obtained during PCI in the catheterization laboratory. Patients were informed about all potential risks associated with the study. The study was registered at ClinicalTrials.gov : NCT04573751. The conduct of the study was approved by the local ethics committee (protocol No. 203 dated 14/10/2020). The study was conducted based on a modified protocol.
Inclusion criteria included STEMI within 24 hours of symptom onset, complicated by refractory no-reflow phenomenon during PCI, and signed informed consent.
Exclusion criteria included refractory cardiogenic shock requiring mechanical circulatory support, patient refusal to participate in the study, absolute contraindications to MRI, and history of anaphylactic reactions to adrenaline.
All participants underwent selective coronary angiography using the Siemens Artis Zee Floor Angioscopy X-ray (Siemens Healthineers, Erlangen, Germany). The no-reflow phenomenon was defined as a reduction in anterograde angiographic blood flow in the infarct-related coronary artery (IRCA) as assessed by the TIMI score of <3 after stent deployment, with the exclusion of cases of stent dissection and acute stent thrombosis. The no-reflow phenomenon was considered refractory when it did not resolve with the use of at least 1 of the following agents: nitroglycerin, adenosine, papaverine, glycoprotein IIB/IIIA inhibitors, and thrombectomy. The initial approach to treat the no-reflow phenomenon was left to the discretion of the operator.
In the event of refractory no-reflow phenomenon development, patients were randomized into groups using sealed envelopes: patients of the first group underwent intracoronary adrenaline administration at the dose of 100 μg through a guiding catheter inserted into IRCA. Patients of the second group (control) received conventional treatments alone (administration of another drug from the list previously mentioned, usually nitroglycerin or glycoprotein IIB/IIIA platelet receptor inhibitor) ( Figure 1 ).
To obtain an adrenaline solution, 1 ml of 0.1% solution was diluted in 50 ml of normal saline (20 μg/ml); 5 ml was then drawn from the resulting solution, containing 100 μg of adrenaline. After preparing the adrenaline solution syringe, slow (>20 to 30 seconds) administration of its contents into the IRCA was performed through a guiding catheter. Continuous monitoring of clinical symptoms and hemodynamic parameters, including systolic and diastolic blood pressure, heart rate (HR), and electrocardiogram, was conducted throughout the procedure.
The initial assessment of coronary blood flow using the TIMI scale was performed by the interventional cardiologist conducting the PCI procedure. Subsequently, all angiograms, both before and after adrenaline administration and in the control group, were evaluated by another experienced interventional cardiologist from an independent institution who was blinded to the group allocation of the patients. The evaluation of the electrocardiography (ECG), both before and after PCI, was carried out by a functional diagnostics physician who was also blinded to the group assignment of the patients. The TIMI blood flow assessment was conducted 2 minutes after the completion of intracoronary administration of adrenaline or the other allocated medication in the control group. ECG were recorded both before the PCI and immediately after its completion (within 10 minutes after PCI).
Before PCI, all patients received aspirin 250 mg, clopidogrel 600 mg or ticagrelor 180 mg, and a bolus of unfractionated heparin 70 to 100 IU/kg, followed by its infusion under activated partial thromboplastin time or activated clotting time control.
Within 1 to 2 days of admission and again on days 7 to 10, all patients underwent transthoracic echocardiography using the Philips CX50 (Philips Healthcare, Amsterdam, Netherlands) ultrasound system equipped with the s5-1 transducer. The examinations were performed by an experienced specialist who was blinded to the results of other studies and patient clinical status. Standard transthoracic echocardiography was conducted following the guidelines of the American Society of Echocardiography. The examination included the acquisition of parasternal long-axis and short-axis views, as well as apical 2-chamber and 4-chamber views. Key measurements included left ventricular ejection fraction (LVEF), LV end-diastolic volume (LVEDV), and LV end-systolic volume (LVESV). Doppler imaging was used to assess valvular function and blood flow velocities.
The wall motion score index (WMSI) was calculated by dividing the LV into 17 segments, as per the American Heart Association 17-segment model. Each segment was evaluated for wall motion and assigned a score: 1 for normal, 2 for hypokinetic, 3 for akinetic, and 4 for dyskinetic. The total score was then divided by the number of segments analyzed to obtain the WMSI. A higher WMSI indicates a more severe impairment of regional wall motion.
A cardiac MRI was performed on a 1.5-T clinical magnetic resonance scanner (Vantage Titan 1.5-T, Canon Medical Systems, Tochigi, Japan). Images were acquired during multiple breath-holds with a cardiac software package. ECG-gated cine images were obtained for functional analysis using a steady-state free precession sequence (slice thickness 8 mm, slice gap 2 mm, average repetition time (TR) = 3.7 and echo time (TE) = 1.9 ms, flip angle 72°, field of view 360 × 360 mm, matrix 240 × 128, 14 phases per cardiac cycle), in the following orientations: 2-chamber long axis, 4-chamber long axis, and a short-axis stack the LV. Before contrast administration, breath-hold T2-weighted spin-echo images were acquired to visualize infarct-related edema in short-axis orientation covering the whole LV. Typical parameters were TR = 1,774 ms; and TE 80 ms. Myocardial edema was defined as an area with a hyperintensive signal and was manually delineated and quantified.
Early and delayed enhancement images of the whole left ventricle were acquired at 1 to 2 and 8 to 15 minutes after intravenous administration of 0.15 to 0.2 mmol/kg gadobutrol (Gadovist, Bayer Healthcare, Berlin, Germany).
Late gadolinium enhancement (LGE) imaging was performed using an inversion recovery gradient echo sequence. The time inversion was selected individually to null normal myocardium. Typical parameters were slice thickness 7 to 10 mm; TR 9.1 mm; TE 3.6 ms; flip angle 17°; and TI 240 to 360 ms.
Semi-automated threshold detection was used to identify regions of edema and infarcted myocardium. Infarct size was measured on the LGE images by a semi-automatic drawing of hyperenhanced areas and expressed as a percentage of LV mass. A myocardial region was regarded as affected if at least 10 adjacent myocardial pixels revealed a signal intensity of >2 SDs of remote myocardium for edema and >5 SDs in LGE images. Contiguous short-axis slices were acquired from the base to the apex for calculation of left ventricular function and mass (CVI42, v5.1.1, Circle Cardiovascular Imaging, Calgary, Ontario, Canada).
The primary end point was achieving TIMI 3 coronary blood flow in the IRCA.
Secondary endpoints included (1) Percentage ratio of MVO volume to LV myocardial mass, as assessed by MRI; (2) size of risk zone according to MRI; (3) presence of myocardial hemorrhagic infiltration (MHI); (4) size of MI on MRI; (5) troponin I level at 12 to 24 hours after admission; (6) resolution of ST-segment elevation on electrocardiography by >50% within 1-hour after PCI; (7) LVEF as assessed by echocardiography on days 1 to 2 and 7 to 10 days after admission; (8) occurrence of life-threatening arrhythmias after adrenaline administration; (9) MACE events within 30 days. MACE events included cases of cardiovascular death, hospitalization for acute heart failure (AHF), and MI. Clinical, laboratory, and instrumental data of patients were retrieved from medical records. 30-day clinical outcomes were obtained through telephone interviews ( Figure 2 ).
The normality of the sample distribution of quantitative variables was assessed using the Shapiro-Wilk test. Variables are presented as mean and standard deviation (m ± SD) in case they are normally distributed, and as median and interquartile range (Q1; Q3) otherwise. Categorical variables were described by absolute and relative frequencies (%). To detect statistically significant differences in quantitative variables between independent groups of patients with different types of treatment, the Student t test was used for normally distributed variables, and Mann-Whitney nonparametric U test was used in the absence of normal distribution. To identify statistically significant dynamic differences in quantitative variables, repeated measures analysis of variance and paired t test were used for normally distributed variables, and Wilcoxon test was used in the absence of normal distribution. Categorical variables in independent groups were compared using the chi-square Pearson test or Fisher’s exact test. The threshold for significance level was set at p = 0.05.
Results
From December 2020 to March 2024, a total of 2104 patients with STEMI underwent emergency PCI in the Cardiology Research Institute. Of them, 268 (13%) patients developed the no-reflow phenomenon. The prevalence of refractory no-reflow phenomenon in patients with STEMI in our study reached 112 (5.3%) cases. Criteria for exclusion were identified in 22 patients. Thirteen patients were diagnosed with refractory cardiogenic shock requiring mechanical circulatory support, whereas 9 had contraindications to MRI. Thus, 90 patients were randomized into 2 groups: 45 patients in Group 1 received adrenaline, and 45 patients in Group 2 (control) received conventional treatments alone without adrenaline ( Figure 1 ).
Except for a predominance of patients with peripheral artery disease in the adrenaline group (89% vs 71% [p = 0.035]), other baseline clinical and anamnestic characteristics did not differ between the groups. There were no differences between the groups regarding the localization of MI, IRCA, TIMI blood flow grade pre-PCI, and Killip class of AHF on admission ( Table 1 ).
| Indicator | Epinephrine n- 45 | Conventional tr treatments n-45 | p |
|---|---|---|---|
| Age, years | 65.0 (±10.0) | 63.0 (±12.0) | 0.490 |
| Male, n (%) | 30 (67.0) | 35 (78.0) | 0.239 |
| Hypertensive heart disease, n (%) | 45 (100) | 42 (93.0) | 0.078 |
| Smoking, n (%) | 22 (49.0) | 28 (62.0) | 0.203 |
| Body mass index, kg/m 2 | 28.0 (25.0; 33.0) | 29.0 (27.0; 32.0) | 0.369 |
| Type 2 diabetes mellitus, IGT, n (%) | 20 (44.0) | 24 (53.0) | 0.399 |
| Dyslipidemia, n (%) | 34 (7.0) | 36 (80.0) | 0.612 |
| Heredity, n (%) | 20 (44.0) | 20 (44.0) | 1.000 |
| History of angina pectoris, n (%) | 6 (13.0) | 8 (18.0) | 0.561 |
| Post-infarction cardiac fibrosis, n (%) | 3 (7.0) | 4 (8.9) | 0.694 |
| Peripheral artery disease, n (%) | 40 (89.0) | 32 (71.0) | 0.035 |
| History of stroke, n (%) | 6 (13.0) | 3 (6.7) | 0.292 |
| AF, n (%) | 5 (11.0) | 6 (13.0) | 0.748 |
| Time from the onset of ACS symptoms, min | 210.0 (154.0; 600.0) | 280.0 (135.0;574.0) | 0.628 |
| Thrombolytic therapy, n (%) | 13 (29.0) | 11 (24.0) | 0.634 |
| Laboratory data upon admission: | |||
| GFR according to CKD-EPI, ml/min/1.73 m2 | 65.0 (±14.0) | 68.0 (±15.0) | 0.373 |
| Leukocytes, count 10^9/L | 12.0 (10.0; 15.0) | 11.0 (9.6; 14.0) | 0.493 |
| ESR, mm/h | 12.0 (7.0; 23.0) | 16.0 (8.0; 28.0) | 0.259 |
| CRP, mg/l | 20.9 (12.0; 40.0) | 19.0 (8.0; 36.0) | 0.482 |
| AHF Platelet, count 10^9/L | 242.0 (202.0 294.0) | 219.0 (194.0 251.0) | 0.195 |
| Glucose, mmol/l | 8.4 (7.4; 11.0) | 9.4 (7.5; 11.0) | 0.404 |
| Cholesterol, mmol/l | 5.0 (4.3; 5.7) | 5.4 (4.6; 6.1) | 0.113 |
| Triglycerides, mmol/l | 1.2 (0.6; 1.9) | 1.6 (0.8; 2.2) | 0.159 |
| grade according to the Killip scale upon admission: | |||
| Killip I, n (%) | 31 (69.0) | 35 (78.0) | 0.340 |
| Killip II, n (%) | 3 (6.7) | 3 (6.7) | 1.000 |
| Killip III, n (%) | 4 (8.9) | 4 (8.9) | 1.000 |
| Killip IV, n (%) | 7 (16.0) | 3 (6.7) | 0.180 |
| Inhibitors P2Y12: | |||
| Cloridogrel, n (%) | 24 (53.0) | 21 (46.0) | 0.399 |
| Ticagrelor, n (%) | 20 (44.0) | 24 (53.0) | 0.399 |
| Prasugrel, n (%) | 1 (2.2) | 0 (0) | 0.315 |
| Parameters for PCI: | |||
| Residual coronary artery stenosis >50%, n (%) | 24 (53.0) | 19 (42.0) | 0.303 |
| Direct stenting, n (%) | 5 (11.0) | 5 (11.0) | 1.000 |
| Infarction related coronary artery: | |||
| LAD, n (%) | 24 (53.0) | 27 (60.0) | 0.523 |
| LCX, n (%) | 4 (8.9) | 4 (8.9) | 1.000 |
| RCA, n (%) | 15 (33.0) | 11 (24.0) | 0.250 |
| PDA, n (%) | 1 (2.2) | 2 (4.4) | 0.557 |
| OM, n (%) | 1 (2.2) | 1 (2.2) | 1.000 |
| Localization of infarction: | |||
| Anterior infarction, n (%) | 25 (56.0) | 27 (60.0) | 0.670 |
| Inferior infarction, n (%) | 20 (44.0) | 18 (40.0) | 0.895 |
| No-reflow treatment methods : | |||
| Thrombaspiration, n (%) | 15 (33.0) | 23 (51.0) | 0.439 |
| Glycoprotein IIb/IIIa Inhibitors, n (%) | 15 (33.0) | 23 (51.0) | 0.071 |
| Papaverine, n (%) | 4 (8.9) | 2 (4.4) | 0.382 |
| Nitroglycerine, n (%) | 39 (87.0) | 32 (71.0) | 0.102 |
| Adenosine, n (%) | 3 (6.7) | 5 (11.0) | 0.439 |
| TIMI blood flow after PCI before epinephrine administration: | |||
| TIMI 0, n (%) | 2 (4.4) | 3 (6.7) | 0.645 |
| TIMI 1, n (%) | 10 (22.0) | 4 (8.9) | 0.081 |
| TIMI 2, n (%) | 33 (73.0) | 38 (84.0) | 0.133 |
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