Previous studies investigating prehospital use of glycoprotein IIb/IIIa inhibitors (GPIs) in patients with ST-segment elevation myocardial infarction reached conflicting conclusions. The benefit of this strategy in addition to in-ambulance loading of dual-antiplatelet therapy remains controversial. The aim of this study was to analyze data from a prospective registry of patients with ST-segment elevation myocardial infarctions admitted <24 hours after symptom onset (July 2006 to May 2012). A total of 2,052 patients managed in a physician-staffed mobile intensive care unit (MICU) <12 hours after symptom onset and scheduled for primary percutaneous coronary intervention (PPCI) were retrospectively included. Patients who received GPIs in the MICU were compared with those who did not. The primary end point was infarct-related artery patency, defined as pre-PPCI Thrombolysis In Myocardial Infarction (TIMI) flow grade 3. GPIs were administered in the MICU to 737 patients (36%), including 430 <2 hours after symptom onset, and 1,315 patients (64%) did not received prehospital GPIs. Pre-PPCI TIMI flow grade 3 rate was lower in patients treated in the MICU (17.2% vs 21.3%, p = 0.03) because of patients treated >2 hours after symptom onset, of whom only 12.7% reached the primary end point. There was no significant difference between groups in the rate of in-hospital major adverse cardiac events. In conclusion, prehospital GPI use in patients with ST-segment elevation myocardial infarctions <12 hours after symptom onset scheduled for PPCI neither improved pre-PPCI infarct-related artery patency nor reduced in-hospital major adverse cardiac events.
Primary percutaneous coronary intervention (PPCI) especially when performed in a timely fashion is the preferred strategy of reperfusion in patients with ST-segment elevation myocardial infarction (STEMI) given its superiority over fibrinolysis in reducing mortality and improving outcomes. The delay related to expanded use of PPCI adversely affects survival and conceptually fits well with the prehospital use of glycoprotein IIb/IIIa inhibitors (GPIs). Several trials predating the routine use of dual-antiplatelet therapy (DAPT) showed benefits on clinical end points of GPIs in addition to heparin in PPCI. The Ongoing Tirofiban in Myocardial Infarction Evaluation 2 (ON-TIME 2) trial demonstrated an improvement in surrogate markers of reperfusion, while the EUROTRANSFER registry and meta-analyses showed improved pre-PPCI epicardial recanalization and long-term survival with upstream compared with standard administration of GPIs without significant difference in major bleeding. Conversely, the Facilitated Intervention With Enhanced Reperfusion Speed to Stop Events trial failed to show any improvement in 90-day clinical outcomes with upstream use of abciximab and resulted in an increased risk for nonintracranial bleeding compared with the use of abciximab in the catheterization laboratory (CL). Moreover, the Bavarian Reperfusion Alternatives Evaluation-3 study did not show any reduction of infarct size from the upstream administration of abciximab in addition to a 600-mg loading dose of clopidogrel before PPCI. Against this background, the purpose of this study was to evaluate the impact of upstream use of GPIs on infarct-related artery (IRA) patency, defined as pre-PPCI Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 (see classification in the Appendix ) in daily practice.
Methods
This retrospective observational study was based on data from the Brittany Regional Infarction Observatory, which prospectively includes all patients with diagnoses of STEMI admitted to any of the 9 participating interventional cardiology centers (see list in the Appendix ) <24 hours after symptom onset. The centralized database used for the present study contains demographic information and comprehensive clinical, electrocardiographic, and procedural data concerning patients with STEMIs. This registry was approved by Commission Nationale de l’Informatique et des Libertés.
Out-of-hospital patients, managed in physician-staffed mobile intensive care units (MICUs), <12 hours after self-reported symptom onset and directly admitted to the CL for PPCI were included in the present study. Exclusion criteria were as follows: fibrinolysis, no reperfusion strategy during the acute phase, delay from symptom onset to first medical contact >12 hours, initial presentation as out-of-hospital cardiac arrest, no direct admission to the CL, unknown timing or place of GPI administration, GPI administration during a secondary percutaneous coronary intervention of the culprit lesion, death before angiography was performed, and unknown pre- or post-PPCI TIMI flow grade in the IRA.
Patients were divided into 2 groups: those who were administered GPIs in the MICU, ≥30 minutes before mechanical reperfusion (prehospital GPIs), and those who were not (no prehospital GPIs). These groups were subsequently divided into 2 subgroups: for the prehospital GPI group, patients with administration delays ≤2 hours (MICU ≤2 hours) or >2 hours (MICU >2 hours) from symptom onset, and for the no prehospital GPI group, those who did not receive GPIs at any time (no GPIs) and those who were administered GPIs immediately before or during PPCI in the CL (GPI in the CL).
The primary end point of the present study was patency of the IRA, defined as pre-PPCI TIMI flow grade 3. The secondary end point was the occurrence of in-hospital major adverse events (MACEs), defined as a composite of all-cause death, recurrent myocardial infarction, or stent thrombosis.
Participating centers’ protocols recommended the use of a loading dose of aspirin (250 to 500 mg intravenously) and 1 of the P2Y 12 receptor antagonists available at the time of inclusion (i.e., clopidogrel 300 to 600 mg or prasugrel 60 mg) together with a bolus dose of either unfractionated heparin (50 to 70 IU/kg intravenously) or low–molecular weight heparin (enoxaparin 0.5 mg/kg intravenously) as soon as possible in the MICU. GPIs were decreasingly used in the MICU over the study period (from 67.9% of patients in 2006 to 12.6% in 2012), with a marked decrease after publication of the 2008 guidelines of the European Society of Cardiology, whereas prasugrel was increasingly used, from 22.8% of patients in 2010 to 55.9% in 2012.
Coronary angiography and PPCI were done according to each institution’s guidelines and standards and were stored on hard disks and analyzed off-line by site operators. Pre- and post-PPCI IRA TIMI flow grades were assessed. Pain-to-diagnosis, pain-to-GPI, and pain-to-balloon times were defined as the time (in minutes) between symptom onset and, respectively, the first electrocardiogram allowing STEMI diagnosis, the GPI bolus, and first balloon inflation or aspiration thrombectomy. Door-to-balloon time was the delay between hospital admission and first balloon inflation or aspiration thrombectomy.
Categorical variables are presented as numbers and proportions; continuous variables were assessed for normality and are reported as median (interquartile range) or mean ± SD as appropriate. Continuous variables were compared using Wilcoxon’s test, and categorical variables were compared using chi-square tests or Fisher’s exact tests. To evaluate the impact of the timing of prehospital administration of GPIs on IRA patency, the percentage of patients with TIMI flow grade 3 were compared using chi-square tests or Fisher’s exact tests. Multivariate logistic regression analysis, including all variables with p values <0.05 in univariate analysis, was performed to take into account potentially confounding variables. To further assess the impact of drug-exposure time, analysis was conducted separating patients according to diagnosis-to-balloon time, with a cutoff of 120 minutes. Similarly, to evaluate the impact of the implementation of the 2008 European Society of Cardiology guidelines in local protocols, analysis was conducted in patients included before and after January 2009. Finally, to evaluate the impact of the availability of prasugrel, analysis was conducted in patients included before and after January 2010. To evaluate the impact of the administration of GPIs along with its timing on in-hospital MACEs, crude relative risks were estimated using no GPIs as a reference. Multivariate logistic regression analysis, including all variables with p values <0.05 in univariate analysis, was performed to take into account potentially confounding variables. Analyses were conducted using SAS version 9.3 (SAS Institute, Inc., Cary, North Carolina). A p value <0.05 was considered statistically significant.
Results
From July 2006 to May 2012, 5,766 patients were included in the Brittany Regional Infarction Observatory, of whom 2,689 (47%) were managed in physician-staffed MICUs <12 hours after symptom onset. Among these patients, 2,052 had no exclusion criteria ( Figure 1 ).
A total of 737 patients (36%) received GPIs in MICUs, and 1,315 patients (64%) formed the group receiving no prehospital GPIs. Half of the prehospital GPI group was included before the publication of 2008 guidelines, whereas 73% of patients in the no prehospital GPI group were included after this publication (p <0.001). Characteristics of the study population and treatment groups are listed in Table 1 . Among prehospital GPI patients, 430 (58%) were treated <2 hours after symptom onset. Patients’ characteristics according to pain-to-GPI time are listed in Table 2 .
| Variable | All Patients (n = 2052) | Pre-Hospital GPI | p-Value | |
|---|---|---|---|---|
| Yes (n = 737) | No (n = 1315) | |||
| Age (years) | 62.3 ± 13.0 | 62.0 ± 12.5 | 62.5 ± 13.2 | 0.49 |
| Female sex | 405 (19.7%) | 125 (17.0%) | 280 (21.3%) | 0.02 |
| Body mass index (kg/m²) | 26.2 ± 4.0 | 26.2 ± 3.9 | 26.2 ± 4.1 | 0.93 |
| Inaugural event | 1686 (82.2%) | 618 (84.0%) | 1068 (81.2%) | 0.15 |
| Myocardial infarction | 160 (7.8%) | 53 (7.2%) | 107 (8.2%) | 0.73 |
| Previous percutaneous coronary intervention | 184 (9.0%) | 62 (8.4%) | 122 (9.3%) | 0.74 |
| Previous stent | 164 (8.0%) | 56 (7.6%) | 108 (8.2%) | 0.48 |
| Coronary artery bypass graft | 20 (1.0%) | 3 (0.4%) | 17 (1.3%) | 0.06 |
| Angina pectoris | 91 (4.4%) | 26 (3.5%) | 65 (5.0%) | 0.25 |
| History of stroke | 66 (3.2%) | 17 (2.3%) | 49 (3.7%) | 0.09 |
| Peripheral artery disease | 75 (3.6%) | 26 (3.5%) | 49 (3.7%) | 0.29 |
| Chronic kidney disease | 28 (1.3%) | 10 (1.4%) | 18 (1.4%) | 1.0 |
| Current smoker | 798 (38.9%) | 279 (38.3%) | 519 (39.6%) | 0.57 |
| Diabetes mellitus | 199 (9.7%) | 57 (7.9%) | 142 (11.0%) | 0.03 |
| Hypertension ∗ | 803 (39.1%) | 276 (37.6%) | 527 (40.2%) | 0.26 |
| Dyslipidemia † | 1002 (48.8%) | 333 (48.5%) | 669 (53.6%) | 0.03 |
| ECG on admission | ||||
| ST segment elevation | 2022 (98.5%) | 725 (98.4%) | 1297 (98.6%) | 0.83 |
| Q wave | 580 (28.2%) | 256 (34.7%) | 324 (24.6%) | <0.001 |
| Anterior myocardial infarction | 885 (43.1%) | 328 (44.5%) | 557 (42.3%) | 0.35 |
| Time delays (minutes) | ||||
| Pain-to-diagnosis time | 80 (50–139.5) | 79 (50–134) | 80 (50–141) | 0.26 |
| Diagnosis-to-balloon time | 88 (75–106) | 91 (79–110) | 85 (72–104) | <0.001 |
| Door-to-balloon time | 32 (25–41) | 34 (25–41) | 32 (25–41) | 0.03 |
| Pain-to-balloon time | 175 (137–236) | 178 (140–235) | 173 (135–239) | 0.35 |
| Pain-to-GPI time | 140 (100–200) | 110 (75–165) | 169 (130–230) | <0.001 |
| GPI-to-balloon time | 35 (3–64) | 63 (52–79) | 3 (−5–13) | <0.001 |
| Diagnosis-to-balloon time <120 | 1323 (64.5%) | 462 (62.7%) | 861 (65.5%) | 0.03 |
| Diagnosis-to-balloon time <90 | 721 (35.1%) | 237 (32.3%) | 484 (36.8%) | 0.01 |
| Treatments | ||||
| Beta-blockers | 329 (16.0%) | 113 (15.3%) | 216 (16.4%) | 0.52 |
| Aspirin | 278 (13.5%) | 89 (12.1%) | 189 (14.4%) | 0.16 |
| Statins | 448 (21.8%) | 156 (21.2%) | 292 (22.2%) | 0.59 |
| Vitamin K antagonists | 60 (2.9%) | 8 (1.1%) | 52 (3.9%) | <0.001 |
| Hemodynamic on admission | ||||
| Killip class > 1 | 179 (8.7%) | 61 (8.3%) | 118 (9.0%) | 0.65 |
| Cardiogenic shock | 44 (2.1%) | 13 (1.8%) | 31 (2.4%) | 0.46 |
| Heart rate (b.p.m) | 75.4 ± 17.6 | 75.3 ± 16.8 | 75.5 ± 18.0 | 0.63 |
| Systolic blood pressure (mm Hg) | 132.0 ± 26.0 | 133.0 ± 26.0 | 131.0 ± 26.0 | 0.18 |
∗ Defined as treatment for hypertension or clinical history of hypertension.
† Defined as lipid-lowering treatment or total cholesterol >2.5 g/L.
| Variables | MICU ≤2h Group (n = 430) | MICU >2H Group (n = 307) | GPI in CL Group (n = 717) | No GPI Group (n = 598) | Overall p-Value |
|---|---|---|---|---|---|
| Age (years) | 61.3 ± 12.2 | 62.9 ± 12.9 | 61.1 ± 12.4 | 64.2 ± 14.0 | <0.001 |
| Female sex | 63 (14.6%) | 62 (20.2%) | 136 (19.0%) | 144 (24.1%) | 0.002 |
| Body mass index (kg/m 2 ) | 26.1 ± 3.8 | 26.4 ± 4.1 | 26.3 ± 3.9 | 26.1 ± 4.3 | 0.30 |
| Inaugural event | 362 (84.4%) | 256 (83.4%) | 585 (81.6%) | 483 (80.8%) | 0.44 |
| Myocardial infarction | 28 (6.5%) | 25 (8.1%) | 53 (7.4%) | 54 (9.0%) | 0.49 |
| Percutaneous coronary intervention | 33 (7.7%) | 29 (9.4%) | 68 (9.5%) | 54 (9.0%) | 0.76 |
| Previous stent | 30 (7.0%) | 26 (8.5%) | 62 (8.6%) | 46 (7.7%) | 0.76 |
| Coronary artery bypass graft | 2 (0.5%) | 1 (0.3%) | 6 (0.8%) | 11 (1.8%) | 0.09 |
| Angina pectoris | 16 (3.8%) | 10 (3.3%) | 35 (4.9%) | 30 (5.0%) | 0.51 |
| History of stroke | 9 (2.1%) | 8 (2.6%) | 17 (2.4%) | 32 (5.4%) | 0.005 |
| Peripheral artery disease | 11 (2.6%) | 15 (4.9%) | 24 (3.3%) | 25 (4.2%) | 0.31 |
| Chronic kidney disease | 4 (0.9%) | 6 (2.0%) | 4 (0.6%) | 14 (2.3%) | 0.03 |
| Current smoker | 164 (38.6%) | 115 (37.8%) | 287 (40.0%) | 232 (38.8%) | 0.36 |
| Diabetes mellitus | 28 (6.6%) | 29 (9.7%) | 73 (10.2%) | 69 (11.5%) | 0.06 |
| Hypertension | 141 (32.8%) | 135 (44.4%) | 269 (37.5%) | 258 (43.1%) | 0.001 |
| Dyslipidemia | 191 (47.7%) | 142 (49.6%) | 381 (53.1%) | 288 (48.2%) | 0.01 |
| Hemodynamic on admission | |||||
| Killip class > 1 | 32 (7.6%) | 29 (9.6%) | 66 (9.2%) | 52 (8.7%) | 0.76 |
| Cardiogenic shock | 5 (1.2%) | 8 (2.6%) | 25 (3.5%) | 6 (1.0%) | 0.007 |
| Heart rate (b.p.m) | 74.1 ± 17.0 | 77.0 ± 16.4 | 75.7 ± 18.0 | 75.1 ± 18.0 | 0.28 |
| Systolic blood pressure (mmHg) | 132 ± 25 | 133 ± 27 | 128 ± 26 | 135 ± 26 | <0.001 |
| ECG on admission | |||||
| ST segment elevation | 421 (97.9%) | 304 (99.0%) | 708 (98.7%) | 589 (98.5%) | 0.45 |
| Q wave | 118 (27.4%) | 138 (44.9%) | 182 (25.4%) | 142 (23.7%) | <0.001 |
| Time delays (minutes) | |||||
| Pain-to-diagnosis time | 55 (35–70) | 148 (110–210) | 67 (40–125) | 70 (41–134) | 0.02 |
| Diagnosis-to-balloon time | 89 (76–107) | 96 (81–116) | 93 (75–115) | 98 (80–125) | 0.46 |
| Pain-to-balloon time | 146 (125–167) | 250 (210–310) | 169 (135–235) | 180 (137–246) | 0.049 |
| Pain-to-GPI time | 80 (60–97) | 176 (150–240) | 169 (130–230) | — | <0.001 |
| GPI-to-balloon time | 63 (51–78) | 64 (53–80) | 3 (−5;13) | — | 0.29 |
| TIMI flow grade 3 before PCI | |||||
| Treatments | 88 (20.5%) | 39 (12.7%) | 116 (16.2%) | 164 (27.4%) | <0.001 |
| Beta-blockers | 67 (15.6%) | 46 (15.0%) | 98 (13.7%) | 118 (19.7%) | 0.02 |
| Aspirin | 47 (10.9%) | 42 (13.7%) | 87 (12.1%) | 102 (17.1%) | 0.02 |
| Statins | 86 (20.0%) | 70 (22.8%) | 159 (22.2%) | 133 (22.2%) | 0.77 |
| Vitamin K antagonists | 6 (1.4%) | 2 (0.7%) | 14 (2.0%) | 38 (6.4%) | <0.001 |
Reflecting differences in inclusion year and the availability of prasugrel, there were significant differences in prehospital treatment between groups, as no prehospital GPI patients were less likely to be given DAPT and heparin in a MICU (p <0.001).
No significant difference in angiographic baseline characteristics (IRA, multivessel disease) between groups was observed. Over the course of the study, the radial access rate increased from 28.6% in 2006 to 62.3% in 2012. Similarly, drug-eluting stents accounted for 10.9% of implanted stents from 2006 to 2009, compared with 18.6% from 2010 to 2012. Reflecting these changes in PPCI practices, radial access and drug-eluting stent implantation were more frequent in the no prehospital GPI group. Fewer PPCI procedures were performed in patients exhibiting pre-PPCI TIMI flow grade 3 in the IRA (83.3% vs 96.4%, p <0.001).
Compared with those managed later, patients managed <2 hours after symptom onset showed a higher rate of pre-PPCI TIMI flow grade 3 (21.2% vs 17.0%, p = 0.03). Proportions of TIMI flow grade 3 in the IRA before PPCI were significantly different between groups ( Figure 2 ): 17.2% in patients who received GPIs in MICUs and 21.3% in those who did not (p = 0.03). The difference remained significant when considering the delay of administration: 12.7% in the MICU >2 hours group, 20.5% in the MICU ≤ 2 hours group, and 21.3% in the no prehospital GPI group (p = 0.003). Two-by-two comparisons showed a significant difference between the MICU ≤2 hours and MICU >2 hours groups (p = 0.006) and between the MICU >2 hours and no prehospital GPI groups (p <0.001) but no significant difference between the MICU ≤2 hours and no prehospital GPI groups (p = 0.71). Table 3 lists angiographic findings. Table 4 lists patients’ characteristics according to pre-PPCI TIMI flow grade in the IRA.
| Variable | All Patients (n = 2052) | Pre-Hospital GPI | p-Value | |
|---|---|---|---|---|
| Yes (n = 737) | No (n = 1315) | |||
| Pre-hospital treatments | ||||
| Aspirin | 1966 (95.8%) | 718 (96.8%) | 1284 (97.6%) | 0.87 |
| Clopidogrel | 1451 (70.7%) | 679 (92.1%) | 772 (58.7%) | <0.001 |
| Prasugrel | 377 (18.4%) | 1 (0.1%) | 376 (28.6%) | <0.001 |
| Aspirin+P2Y12 receptor antagonist | 1776 (86.5%) | 670 (90.9%) | 1106 (84.1%) | <0.001 |
| Aspirin+Clopidogrel | 1409 (68.7%) | 669 (90.8%) | 740 (56.3%) | <0.001 |
| Aspirin+Prasugrel | 367 (17.9%) | 1 (0.1%) | 366 (27.8%) | <0.001 |
| Low-molecular weight/unfractionated heparin | 1952 (95.1%) | 715 (97.0%) | 1237 (94.1%) | 0.004 |
| Glycoprotein IIb/IIIa inhibitor | ||||
| Abciximab | 1232 (60.0%) | 725 (98.4%) | 507 (38.6%) | <0.001 |
| Eptifibatide | 2 (0.1%) | 1 (0.1%) | 1 (0.01%) | 1.0 |
| Tirofiban | 145 (7.0%) | 7 (0.9%) | 138 (10.5%) | <0.001 |
| Angiography | ||||
| Radial access | 779 (38.0%) | 230 (31.2%) | 549 (41.7%) | <0.001 |
| Infarct related coronary artery | ||||
| Left anterior descending | 865 (42.1%) | 322 (43.7%) | 543 (41.3%) | 0.51 |
| Left Circumflex | 287 (14.0%) | 98 (13.3%) | 189 (14.4%) | 0.80 |
| Right | 869 (42.3%) | 309 (41.9%) | 560 (42.6%) | 0.94 |
| Left main coronary artery (LMCA) | 23 (1.1%) | 3 (0.4%) | 20 (1.4%) | 0.06 |
| Bypass graft | 3 (0.1%) | 0 | 3 (0.2%) | 0.32 |
| Three-vessel disease or LMCA | 395 (19.2%) | 131 (17.8%) | 264 (20.0%) | 0.20 |
| TIMI flow at initial angiography | <0.001 | |||
| 0 | 1155 (56.3%) | 376 (51.0%) | 779 (59.2%) | |
| 1 | 203 (9.9%) | 96 (13.0%) | 107 (8.1%) | |
| 2 | 282 (13.7%) | 126 (17.1%) | 156 (11.9%) | |
| 3 | 407 (19.8%) | 127 (17.2%) | 280 (21.3%) | 0.03 |
| 2 or 3 | 689 (33.6%) | 436 (33.2%) | 253 (34.3%) | 0.59 |
| Primary PCI performed | 1924 (93.8%) | 687 (93.2%) | 1237 (94.1%) | 0.64 |
| PCI Failure | 45 (2.2%) | 18 (2.4%) | 27 (2.1%) | 0.52 |
| Multivessel PCI | 83 (4.0%) | 36 (4.9%) | 47 (3.6%) | 0.23 |
| Complete revascularization | 1012 (49.3%) | 376 (51.0%) | 636 (48.4%) | 0.19 |
| Stent implantation | 1799 (87.7%) | 645 (87.5%) | 1154 (87.8%) | 0.93 |
| Drug-eluting stent implantation | 261 (12.7%) | 71 (9.6%) | 190 (14.4%) | 0.002 |
| Additional devices | ||||
| Aspiration thrombectomy | 1050 (51.2%) | 360 (48.8%) | 690 (52.5%) | 0.27 |
| IABP or ECMO | 89 (4.3%) | 33 (4.5%) | 56 (4.3%) | 0.82 |
| Temporary pacemaker | 9 (0.4%) | 6 (0.8%) | 3 (0.2%) | 0.08 |
| TIMI flow after PCI | 0.59 | |||
| 0 | 26 (1.3%) | 11 (1.5%) | 15 (1.1%) | |
| 1 | 11 (0.5%) | 4 (0.5%) | 7 (0.5%) | |
| 2 | 47 (2.3%) | 21 (2.8%) | 26 (2.0%) | |
| 3 | 1840 (89.7%) | 651 (88.3%) | 1189 (90.4%) | 0.16 |
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