The goal of this study was to characterize determinants of infarct size in the multicenter randomized Counterpulsation to Reduce Infarct Size Pre-PCI Acute Myocardial Infarction (CRISP-AMI) trial. Contemporary determinants of infarct size in patients presenting with acute anterior myocardial infarction without shock and undergoing percutaneous revascularization have been incompletely characterized. In CRISP-AMI, 337 patients with acute anterior ST segment elevation myocardial infarction but without cardiogenic shock at 30 sites in 9 countries were randomized to initiation of intra-aortic balloon counterpulsation before primary percutaneous coronary intervention versus standard of care. The primary outcome was infarct size as measured by cardiac magnetic resonance imaging 3 to 5 days after percutaneous coronary intervention. Of 337 randomized patients, complete periprocedural and infarct size data were available in 250 patients (74%). After a comparison of baseline characteristics to ensure no significant differences, patients with missing data were excluded. Using multiple linear regression of 23 variables, time from symptom onset to first device (β = 0.022, p = 0.047) and preprocedural Thrombolysis In Myocardial Infarction flow 0/1 (β = 15.28, p <0.001) were independent predictors of infarct size. Infarct size increased by 0.43% per 30 minutes in early reperfusion and by 0.63% every 30 minutes in late reperfusion. In conclusion, in patients with acute anterior ST elevation myocardial infraction without cardiogenic shock, total ischemic time and preprocedural Thrombolysis In Myocardial Infarction flow 0/1 were associated with increased infarct size as determined by cardiac magnetic resonance imaging. These findings underscore the importance of systems of care aimed at reducing total ischemic time to open infarct arteries.
The recently reported Counterpulsation to Reduce Infarct Size Pre-PCI Acute Myocardial Infarction (CRISP-AMI) trial was a randomized controlled trial of intra-aortic balloon counterpulsation (IABC) before percutaneous coronary intervention (PCI) versus PCI alone for anterior wall ST elevation myocardial infarction (STEMI). The primary end point was infarct size as determined by cardiac magnetic resonance imaging (CMRI). The aim of the present study was to assess predictors of infarct size in the multicenter multinational CRISP-AMI trial.
Methods
The methods used in the CRISP-AMI trial have been previously reported. Briefly, CRISP-AMI was a prospective, open, international, multicenter (n = 30) randomized controlled trial to determine if a routine strategy of IABC insertion before primary PCI reduced infarct size in patients with acute anterior STEMI without cardiogenic shock. Patients in the standard of care group of the trial received primary PCI without planned IABC support.
Institutional review boards and ethics committees approved the trial, and each enrolled patient provided written informed consent. The Duke Clinical Research Institute (Durham, North Carolina) coordinated the trial and carried out the data management and analyses with oversight from the steering committee.
To determine if IABC reduces infarct size, a population of adult patients within 6 hours of chest pain onset and planned primary PCI for acute anterior STEMI with significant myocardium at risk were sought for inclusion into the study. Patients with indications for planned IABC insertion, such as cardiogenic shock, inability to undergo IABC implantation, fibrinolysis within 72 hours of presentation, or known contraindication for CMRI for end point assessment, were excluded. Because the primary end point was infarct size, patients with known previous myocardial infarction or coronary artery bypass graft surgery were also excluded.
The interventions and procedures used in the CRISP-AMI trial have been previously reported. Briefly, patients were randomized to prereperfusion initiation of IABC and mechanical reperfusion with PCI (IABC plus PCI) or primary PCI alone. To ensure rapid reperfusion, sites with demonstrated ability to meet guideline standards were chosen (median door-to-device times <90 minutes). For participants randomized to receive IABC plus PCI, balloon counterpulsation was recommended for ≥12 hours with a maximum of 24 hours after PCI. For patients with hemodynamic instability, counterpulsation could be continued for longer periods at the discretion of the investigators. CMRI was recommended from 3 to 5 days after PCI.
The CMRI protocol to determine infarct size has been described. In general, CMRI using standard sequences was performed for microvascular obstruction, area at risk, left ventricle (LV) dimensions, and function. Delayed-enhancement infarct size imaging was performed after intravenous administration of 0.15 to 0.20 mmol of gadolinium-chelate administered per kilogram of body weight. A central CMRI laboratory at the University of Leipzig Heart Center (Leipzig, Germany) qualified participating sites, performed quality assessment on images during the conduct of the study, and manually performed blinded assessment for LV myocardial mass, microvascular obstruction, area at risk, and infarct size. Myocardial salvage index (MSI) was calculated as: area at risk − infarct size/area at risk × 100.
Baseline characteristics and procedural characteristics were described by quartile of infarct size using median and twenty-fifth and seventy-fifth percentiles for continuous variables; frequencies and proportions were used for categorical variables. To account for missing infarct size data, baseline characteristics of patients with and without CMRI infarct size data were compared to ensure no significant differences. The comparisons were based on the trend test taking into account the order of quartiles of infarct size. All statistical comparisons were performed using 2-sided significance tests and were considered significant at p ≤0.05. After ensuring no significant differences, patients with missing CMRI infarct size data were excluded.
To determine predictors of infarct size, multiple linear regression models of infarct size were constructed using 23 variables. The stepwise model selection method was used for identifying the predictors in the final model. The general assumptions such as normality and linearity were assessed to ensure the validity of the model. The multicollinearity for each predictor was evaluated using variance inflation factor. Unusual and influential data points were checked using statistical measurements (i.e., Cook’s distance), and 1 influential data point was excluded from the analysis.
To account for significant regional variation in the use of bivalirudin, a term for regional interaction with bivalirudin was added to the multiple linear regression model.
To determine the relation between myocardial perfusion index and infarct size as well as infarct size and total ischemic time, a linear trend test was performed for location shift.
To determine the effect of early versus late reperfusion on infarct size, subjects were divided into those who underwent reperfusion before and after 3 hours and a 2-sample t test was applied. Subsequent determination of the change in infarct size per minute of ischemic time was based on the region-adjusted multivariate regression model aforementioned. All statistical analyses were performed using SAS, version 9.2 (SAS Institute Inc., Cary, North Carolina).
Results
A total of 337 patients with anterior STEMI without shock were randomized and enrolled in the CRISP-AMI study at 30 sites in 9 countries from June 2009 through February 2011. Of these, infarct size data, as determined by CMRI, were available in 275 patients (82%). Infarct size as determined by CMRI and complete periprocedural characteristics were available in 250 patients (74%).
There was a significant difference in presenting systolic blood pressure between quartiles of infarct size; however, all other baseline characteristics were similar between infarct size quartiles ( Tables 1 and 2 ). Procedurally, there were significant differences in the use of IABC, infarct-related artery (IRA), stenosis location, preintervention Thrombolysis In Myocardial Infarction (TIMI) grade, time from first medical contact to first device, and time from symptom onset to first device. Finally, due in part to regional differences in medication use, there was a significant difference in unfractionated heparin, bivalirudin, and prasugrel use among different infarct size quartiles.
| Variable | Quartile Infarct (Percent LV) | p | |||
|---|---|---|---|---|---|
| First (n = 69) | Second (n = 69) | Third (n = 69) | Fourth (n = 68) | ||
| Age (yrs) | 55.8 (48.1, 65.7) | 54.3 (45.9, 65.0) | 56.1 (48.9, 63.5) | 56.6 (49.1, 62.4) | 0.921 |
| Men | 54 (78) | 57 (83) | 55 (78) | 56 (82) | 0.900 |
| Race | 0.133 | ||||
| American Indian/Alaska Native | 0 | 0 | 0 | 1 (2) | |
| Asian | 17 (25) | 32 (46) | 36 (52) | 41 (60) | |
| Black | 3 (4) | 3 (4) | 4 (6) | 3 (4) | |
| White | 45 (65) | 33 (48) | 28 (41) | 22 (32) | |
| Other | 4 (6) | 1 (1) | 1 (1) | 1 (2) | |
| Height (cm) | 173.0 (167.6, 178.0) | 167.0 (162.0, 177.8) | 170.0 (165.0, 175.3) | 170.0 (162.0, 174.0) | 0.081 |
| Weight (kg) | 78.0 (65.9, 87.0) | 74.0 (65.0, 85.0) | 75.0 (65.0, 89.5) | 72.5 (65.0, 85.0) | 0.651 |
| Previous PCI | 2 (3) | 1 (1) | 0 | 2 (3) | 0.521 |
| Hypertension (receiving drug therapy) | 22 (32) | 20 (29) | 18 (26) | 21 (31) | 0.886 |
| Stroke | 0 | 0 | 0 | 1 (2) | 0.385 |
| Transient ischemic attack | 0 | 1 (1) | 0 | 0 | 0.394 |
| Current nicotine use | 25 (36) | 26 (38) | 23 (33) | 18 (26) | 0.517 |
| Dyslipidemia (receiving drug therapy) | 12 (17) | 8 (12) | 7 (10) | 9 (13) | 0.620 |
| Previous atrial fibrillation | 1 (1) | 3 (4) | 0 | 0 | 0.110 |
| Renal insufficiency | 2 (3) | 0 | 2 (3) | 0 | 0.260 |
| Diabetes mellitus | 9 (13) | 12 (17) | 14 (20) | 15 (22) | 0.544 |
| Insulin dependent | 3 (33) | 0 | 1 (7) | 3 (20) | 0.131 |
| Non–insulin dependent | 6 (67) | 12 (100) | 13 (93) | 12 (80) | 0.131 |
| Previous peripheral arterial disease | 0 | 0 | 0 | 0 | |
| Presenting systolic blood pressure | 130.0 (116.0, 150.0) | 134.0 (120.0, 150.0) | 138.0 (121.0, 160.0) | 128.0 (110.0, 141.0) | 0.046 |
| Presenting diastolic blood pressure | 78.0 (70.0, 90.0) | 80.0 (70.0, 92.0) | 90.0 (80.0, 96.0) | 80.0 (70.0, 90.0) | 0.072 |
| Heart rate | 78.0 (69.0, 88.0) | 79.0 (64.0, 92.0) | 82.0 (75.0, 91.0) | 80.0 (71.5, 94.0) | 0.489 |
| Degree of ST elevation in anterior leads (mm) | 0.370 | ||||
| 0 to <2 | 0 | 0 | 0 | 0 | |
| 2 to <4 | 0 | 0 | 1 (1.4) | 0 | |
| 4 to <6 | 22 (32) | 31 (45) | 29 (42) | 28 (41) | |
| ≥6 | 47 (68) | 38 (55) | 39 (56) | 40 (59) | |
| Variable | Quartile Infarct (Percent LV) | p | |||
|---|---|---|---|---|---|
| First (n = 69) | Second (n = 69) | Third (n = 69) | Fourth (n = 68) | ||
| Intra-aortic balloon pump placement | 34 (49) | 25 (36) | 37 (54) | 44 (65) | 0.010 |
| PCI | |||||
| Performed | 63 (91) | 67 (97) | 66 (96) | 67 (98) | 0.187 |
| Not performed | 6 (9) | 2 (3) | 3 (4) | 1 (2) | 0.187 |
| Coronary artery bypass grafting instead | 0 | 0 | 2 (3) | 0 | 0.112 |
| No infarct artery identified | 4 (6) | 0 | 0 | 0 | 0.007 |
| Technical limitations | 2 (3) | 2 (3) | 1 (1) | 1 (2) | 0.882 |
| IRA | 0.002 | ||||
| Left main | 0 | 0 | 0 | 0 | |
| Left anterior descending | 64 (92.8) | 69 (100.0) | 69 (100.0) | 68 (100.0) | |
| Left circumflex | 0 | 0 | 0 | 0 | |
| Right coronary | 1 (1) | 0 | 0 | 0 | |
| No IRA identified | 4 (6) | 0 | 0 | 0 | |
| IRA stenosis location | |||||
| Proximal | 37 (57) | 35 (51) | 48 (70) | 48 (71) | 0.042 |
| Mid | 33 (51) | 33 (48) | 21 (30) | 23 (34) | 0.037 |
| Distal | 5 (8) | 3 (4) | 8 (12) | 1 (2) | 0.085 |
| IRA TIMI flow | |||||
| Preintervention grade | <0.001 | ||||
| 0 | 29 (45) | 52 (75) | 49 (71) | 54 (79) | |
| 1 | 5 (8) | 6 (9) | 7 (10) | 3 (4) | |
| 2 | 20 (31) | 6 (9.0) | 7 (10) | 8 (12) | |
| 3 | 11 (17) | 5 (7) | 6 (9) | 3 (4) | |
| Postintervention grade | 0.855 | ||||
| 0 | 0 | 1 (1) | 1 (2) | 1 (2) | |
| 1 | 0 | 1 (1) | 1 (2) | 2 (3) | |
| 2 | 4 (6.3) | 0 | 2 (3) | 1 (2) | |
| 3 | 60 (94) | 67 (97) | 64 (94) | 63 (94) | |
| Interventions performed on non-IRAs | 1 (2) | 2 (3) | 0 | 2 (3) | 0.541 |
| Left main | 1 (100) | 1 (50) | 0 | 0 | 0.311 |
| Left circumflex | 0 | 0 | 0 | 1 (50) | 0.472 |
| Right coronary | 0 | 1 (50) | 0 | 1 (50) | 0.717 |
| Time to treatment | |||||
| From symptom onset to first hospital contact (min) | 103.0 (62.0, 175.0) | 116.0 (67.0, 166.0) | 120.0 (75.0, 175.0) | 110.0 (60.0, 186.0) | 0.622 |
| From first medical contact to first device (IRA) (min) | 65.0 (45.0, 90.0) | 71.0 (44.0, 115.0) | 75.0 (45.0, 88.0) | 77.0 (58.0, 139.0) | 0.028 |
| From symptom onset to first device (IRA) (min) | 170.0 (131.0, 240.0) | 215.0 (153.0, 292.0) | 193.0 (135.0, 252.0) | 230.0 (140.5, 299.0) | 0.013 |
| First device used on IRA | 0.999 | ||||
| Atherectomy/Thrombectomy | 23 (36) | 25 (37) | 24 (36) | 24 (36) | |
| Balloon | 30 (48) | 30 (45) | 33 (50) | 32 (50) | |
| Stent | 10 (16) | 12 (18) | 10 (15) | 11 (16) | |
| Type of stent | 61 (97) | 64 (96) | 65 (97) | 65 (96) | 0.952 |
| Drug-eluting | 31 (51) | 32 (50) | 31 (48) | 29 (45) | 0.889 |
| Bare-metal | 31 (51) | 33 (52) | 35 (54) | 37 (57) | 0.917 |
| Anticoagulant use | |||||
| Unfractionated heparin | 44 (64) | 55 (80) | 59 (86) | 56 (83) | 0.011 |
| Bivalirudin | 22 (32) | 9 (13) | 9 (13) | 7 (10) | 0.002 |
| Glycoprotein IIb/IIIa inhibitor | 25 (36) | 35 (51) | 31 (45) | 36 (53) | 0.204 |
| Periprocedure medications | |||||
| Aspirin | 43 (62) | 37 (54) | 40 (58) | 41 (60) | 0.757 |
| Nitroglycerin | 31 (45) | 34 (50) | 35 (51) | 29 (43) | 0.763 |
| Enoxaparin | 9 (13) | 7 (10) | 4 (6) | 7 (10) | 0.554 |
| Clopidogrel | 35 (51) | 40 (58) | 33 (48) | 37 (54) | 0.657 |
| Ticlopidine | 0 | 0 | 0 | 0 | |
| Prasugrel | 16 (23) | 3 (4) | 10 (14) | 9 (13) | 0.016 |
| Statin | 21 (30) | 27 (39) | 29 (42) | 33 (48) | 0.186 |
| β Blocker | 13 (19) | 17 (25) | 21 (30) | 26 (38) | 0.073 |
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