Comparative Significance of Invasive Measures of Microvascular Injury in Acute Myocardial Infarction

Supplemental Digital Content is available in the text.


Eligibility Criteria
Patients with a clinical diagnosis of acute ST-segment elevation myocardial infarction (STEMI) were eligible for randomization according to the following eligibility criteria:

Inclusion
• Acute MI (symptom onset ≤ 6 hours) with persistent ST-segment elevation or recent left bundle branch block • Coronary artery occlusion (TIMI [Thrombolysis in Myocardial Infarction] coronary flow grade 0 or 1), or impaired coronary flow (TIMI coronary flow grade 2, slow but complete filling) in the presence of definite angiographic evidence of thrombus (TIMI grade 2 or more) • Proximal-mid culprit lesion location in a major coronary artery (i.e. the right, left anterior descending, intermediate, or circumflex artery) • Radial artery access • Successful coronary reperfusion (TIMI coronary flow grade ≥2) pre-stent achieved prior to randomization.
• Informed consent, i.e. only patients who were sufficiently well to understand the information about the study, as described by the attending cardiologist, were eligible to participate.

Exclusion
• Normal flow in the culprit coronary artery at initial angiography (TIMI grade 3) • Functional coronary collateral supply (Rentrop grade 2/3) to the culprit artery • Previous infarction in the culprit artery (known or suspected clinically, e.g. wall motion abnormality revealed by echocardiography • Cardiogenic shock (Killip Class IV) • Multivessel percutaneous coronary intervention (PCI) intended before the day 2-7 cardiovascular magnetic resonance (CMR) scan • Estimated body weight <60 kg • Previous randomization to this study, or participation in a study with an investigational drug, or medical device within 90 days prior to randomization • Women of child bearing potential (i.e. pre-menopausal), or breast feeding • Requirement for immunosuppressive therapy at any time during the preceding 3 months. This would include corticosteroids (but not inhaled or topical), drugs used following transplantation (e.g tacrolimus, cyclosporine), anti-metabolite therapies (e.g. mycophenolic acid, azathioprine, leflunomide and immunomodulators including biologics (e.g. adalimumab, or etanercept) and disease modifying anti-rheumatic drugs. This list is not exhaustive.
• Active or prophylactic treatment with oral, or parenteral antibiotic, antifungal, or antiviral therapy, to prevent or treat infection • Any anti-cancer treatment (excluding surgery as this is covered above) at any time during the preceding 3 months, including chemotherapy, radiotherapy, and treatment with biologics, such as Vascular Endothelial Growth Factor Receptor (VEGFR) inhibitors (e.g. bevacizumab, pazopanib). This list is not exhaustive.
• Any significant concurrent, or recent condition(s) not listed above that in the opinion of the treating clinician would pose an additional risk to the patient.

Angiogram Acquisition and Analysis Methods
Coronary angiograms were acquired during emergency care with cardiac catheter laboratory Xray and information technology equipment. The angiograms were analyzed using post-processing software (QAngio® XA Medis, Leiden, NL.) by experienced investigators who were blinded to treatment allocation. Catheter calibration was performed using the catheter calibration function on MEDIS QAngio. For each lesion, a view perpendicular to the long axis of the vessel was used in order to avoid foreshortening and overlap of branches. The single plane projection showing the best opacified and most severe lesion with minimal foreshortening and minimal branch overlap was selected.
Feedback was provided to sites on the quality and completeness of the angiograms.

TIMI Coronary Flow Grade
The TIMI coronary flow grade was assessed using the following definitions 1 : TIMI coronary flow grade Definition 3 Myocardial blush is present in the distribution of the culprit artery, with normal entry and exit of dye (mild/ moderate persistence of dye beyond 3 cardiac cycles, but notably reduced after 3 cardiac cycles). Blush that is only mild intensity throughout 3 cardiac cycles after injection (washout phase), but fades minimally is also classified as grade 3. 8

TIMI Frame Count
The TIMI frame count represents the amount of time (in frames) for contrast dye to reach a standardized distal landmark 2 . If the culprit vessel was the left anterior descending artery the frame count was divided by 1.7 (correcting for longer vessel length).    Supplemental Table 5. Associations of coronary physiology and angiogram parameters with microvascular obstruction extent, or myocardial hemorrhage extent from linear regression and their associations with microvascular obstruction, or myocardial hemorrhage, presence from logistic regression. Different dichotomizations for IMR, CFR and RRR are shown, including according to median values and according to the optimal thresholds from AUCs. Results are reported as regression coefficient or odds ratio, with 95% confidence interval and p-value.

TIMI Coronary Thrombus Grade
Microvascular obstruction extent and myocardial haemorrhage extent (2-7 days post-PCI) were analysed on square root scales. *CFR≤1.8 was the optimal threshold from AUC for predicting heart failure hospitalization; CFR≤1.3 was the optimal threshold from AUC for all-cause death and heart failure hospitalization; CFR≤1.3 was the optimal threshold from AUC for major adverse cardiac events. †RRR≤1.6 was the optimal threshold from AUC for predicting heart failure hospitalization; CFR≤1.6 was optimal threshold from AUC for predicting all cause death of heart failure hospitalization; CFR≤2.2 was the optimal threshold for predicting major adverse cardiac events.
AUC, area under the curve; CFR, Coronary flow reserve; IMR, index of microcirculatory resistance; RRR, resistive reserve ratio.