Rapid reperfusion with primary percutaneous coronary intervention improves survival in patients with ST-segment elevation myocardial infarction. Preprocedural cardiopulmonary instability and adverse events (IAE) may delay reperfusion time and worsen prognosis. The aim of this study was to evaluate the relation between preprocedural cardiopulmonary IAE, door-to-balloon time (DBT), and outcomes in the Harmonizing Outcomes With Revascularization and Stents in AMI (HORIZONS-AMI) trial. Preprocedural cardiopulmonary IAE included sustained ventricular or supraventricular tachycardia or fibrillation requiring cardioversion or defibrillation, heart block or bradycardia requiring pacemaker implantation, severe hypotension requiring vasopressors or intra-aortic balloon counterpulsation, respiratory failure requiring mechanical ventilation, and cardiopulmonary resuscitation. Three-year outcomes of patients with and without IAE according to DBT were compared. Among 3,602 patients, 159 (4.4%) had ≥1 IAE. DBT did not differ significantly in patients with and without IAE; however, patients with IAE were less likely to have Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow after percutaneous coronary intervention. Mortality at 3 years was significantly higher in patients with versus those without IAE (17.0% vs 6.3%, p <0.0001), and IAE was an independent predictor of mortality, whereas DBT was not. However, a significant interaction was present such that 3-year mortality was reduced in patients with DBT <99 minutes (the median) versus ≥99 minutes to a greater extent in patients with IAE (9.9% vs 20.7%, hazard ratio 0.43, 95% confidence interval 0.16 to 1.16) compared with those without IAE (5.0% vs 7.2%, hazard ratio 0.69, 95% confidence interval 0.50 to 0.95) (p for interaction = 0.004). In conclusion, IAE before PCI is an independent predictor of death and identifies a high-risk group in whom faster reperfusion may be particularly important to improve survival.
Highlights
Preprocedural cardiopulmonary IAE before primary PCI for STEMI were defined in the HORIZONS-AMI trial as sustained ventricular or supraventricular tachycardia or fibrillation requiring cardioversion or defibrillation, heart block or bradycardia requiring pacemaker implantation, severe hypotension requiring vasopressors or intra-aortic balloon counterpulsation, respiratory failure requiring mechanical ventilation, and cardiopulmonary resuscitation. IAE before PCI is an independent predictor of death and identifies a high-risk group in whom faster reperfusion may be particularly important to improve survival.
Early reperfusion with primary percutaneous coronary intervention (PCI) offers the best chance to reduce mortality, infarct size and new onset heart failure in patients with acute ST-elevation myocardial infarction (STEMI). However, the “rush to reperfusion” may interfere with the diagnosis of important co-morbidities or medical stabilization, which may affect the outcomes of PCI. In the past 2 decades, significant national reductions in door-to-balloon time (DBT) have occurred. Yet this impressive decrease in DBT has not correlated with further reductions in in-hospital or 30-day mortality.
Previous studies have suggested that short DBTs may be especially important in high-risk patients. Patients presenting with hypotension and major arrhythmic or respiratory complications are intuitively high risk and may require substantial time for medical stabilization, although, surprisingly, the outcomes of such patients have rarely been examined. Using the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial database, we therefore sought to determine the outcomes of patients presenting with cardiopulmonary instability and the impact of DBT on outcomes in such patients.
Methods
The HORIZONS-AMI trial design and results have been reported in detail. In brief, 3,602 patients with STEMIs <12 hours in duration were randomized in an open-label fashion to bivalirudin or to heparin plus a glycoprotein IIb/IIIa inhibitor during primary PCI. A second randomization was performed in 3,006 patients eligible for stenting to a paclitaxel-eluting stent or an identical bare-metal stent. Clinical follow-up was performed at 30 days, 6 months, 1 year, and then yearly through 3 years. Primary and major secondary end point events, including death, reinfarction, stroke, ischemia-driven target vessel revascularization, stent thrombosis, and bleeding, were adjudicated by a clinical events committee blinded to patient allocation. Major adverse cardiac events (MACEs) were defined as the composite occurrence of death, myocardial infarction, ischemic target vessel revascularization, or stroke. Net adverse clinical events were defined as the composite occurrence of MACE or major bleeding unrelated to coronary artery bypass grafting.
Data regarding clinical, electrical, and hemodynamic stability before cardiac catheterization were prospectively recorded in the detailed electronic case report form. Patients were defined as having preprocedural instability or adverse events (IAE) if ≥1 of the following conditions were present: sustained ventricular tachycardia or fibrillation requiring cardioversion or defibrillation, supraventricular tachycardia requiring cardioversion, heart block or bradycardia requiring pacemaker implantation, severe hypotension requiring vasopressors or intra-aortic balloon counterpulsation, respiratory failure requiring mechanical ventilation, or cardiopulmonary resuscitation.
Outcomes were examined in patients according to the presence or absence or IAE. We further divided each group into those with DBT less than and greater than the median for the entire study and again compared their baseline characteristics and outcomes. For the latter analyses, we included only patients for whom PCI was performed and DBT was available, representing about 75% of the entire study population.
Continuous variables are presented as medians with interquartile ranges (IQRs) and were compared with Wilcoxon’s rank-sum tests. Categorical variables are presented as proportions and were compared with chi-square or Fisher’s exact tests. Event rates were estimated using the Kaplan-Meier time-to-event methodology and compared using log-rank tests. A multivariate logistic regression model was developed to test the independent impact of IAE and DBT on 3-year mortality. In addition to these, the following covariates were considered: age, gender, diabetes mellitus, hypertension, smoking, hyperlipidemia, peripheral arterial disease, chronic kidney disease (creatinine clearance <60 ml/min), previous myocardial infarction, previous PCI, previous bypass surgery, previous heart failure, Killip class I versus II to IV, final Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow (vs 0 to 2 by core laboratory interpretation), infarct artery (left anterior descending coronary artery vs others), and the ejection fraction (a model without the latter was also performed, as nearly 400 patients did not have the ejection fraction assessed). An interaction term, IAE × DBT, was added to the model. The significance level was set at 0.05. All analyses were performed with SAS version 9.2 (SAS Institute Inc, Cary, North Carolina).
Results
Of 3,602 patients enrolled in the study, 159 patients (4.4%) had ≥1 preprocedural IAE (total of 216 IAE), including hypotension requiring intravenous vasopressors (n = 40 [25.2% of all IAE]), hypotension requiring intra-aortic balloon counterpulsation (n = 12 [7.5%]), sustained ventricular tachycardia or fibrillation requiring defibrillation or cardioversion (n = 78 [49.1%]), atrial fibrillation or supraventricular tachycardia requiring cardioversion (n = 6 [3.8%]), heart block or bradycardia requiring pacemaker (n = 47 [29.6%]), respiratory failure requiring mechanical ventilation (n = 10 [6.3%]), and cardiopulmonary resuscitation (n = 23 [14.4%]).
Baseline and procedural characteristics of patients with and without IAE are listed in Table 1 . There were no significant differences in allocation to either randomization stratum between the groups. Patients with IAE were older, were more likely to have previous arrhythmias and peripheral vascular disease, and were more likely to present in Killip class II or higher heart failure. DBT did not differ significantly in patients with and without IAE, although delays from symptom onset to hospital arrival and total ischemic times were significantly lower in patients with IAE, likely because of earlier presentation related to cardiopulmonary instability.
| Variable | Any IAE (N = 159) | Others (N = 3443) | p Value |
|---|---|---|---|
| Age (years) | 62.4 [53.4, 72.8] | 60.1 [52.4, 69.7] | 0.04 |
| Men | 80.5% (128/159) | 76.4% (2632/3443) | 0.24 |
| Hypertension (by history) | 54.1% (86/159) | 53.4% (1838/3440) | 0.87 |
| Hyperlipidemia (by history) | 40.9% (65/159) | 43.2% (1485/3440) | 0.57 |
| Smoking | 69.9% (109/156) | 63.3% (2169/3425) | 0.10 |
| Diabetes mellitus | 17.6% (28/159) | 16.4% (565/3440) | 0.69 |
| Insulin-treated | 3.1% (5/159) | 4.5% (154/3440) | 0.42 |
| Prior myocardial infarction | 13.8% (22/159) | 10.8% (370/3440) | 0.22 |
| Prior coronary intervention | 15.2% (24/158) | 10.5% (362/3440) | 0.06 |
| Prior coronary bypass surgery | 5.0% (8/159) | 2.8% (97/3440) | 0.14 |
| Prior heart failure | 3.1% (5/159) | 2.9% (99/3440) | 0.81 |
| Killip Class | |||
| 1 | 80.5% (128/159) | 92.0% (3159/3433) | <0.0001 |
| 2 | 11.3% (18/159) | 6.6% (228/3433) | 0.02 |
| 3 | 2.5% (4/159) | 0.8% (29/3433) | 0.06 |
| 4 | 5.7% (9/159) | 0.5% (17/3433) | <0.0001 |
| Prior major cardiac rhythm/rate disturbance | 8.8% (14/159) | 2.8% (95/3440) | 0.0003 |
| Prior peripheral vascular disease | 8.2% (13/158) | 4.3% (147/3440) | 0.02 |
| Prior renal insufficiency | 5.1% (8/158) | 2.8% (98/3440) | 0.14 |
| Symptom onset to study hospital (minutes) | 109 [62, 204] | 130 [75, 240] | 0.01 |
| Cath lab arrival to sheath placement (minutes) | 12 [7, 19] | 10 [6, 17] | 0.16 |
| Door to first device (minutes) | 95 [77, 140] | 99 [73, 135] | 0.88 |
| Symptom onset to first device (minutes) | 197 [155, 293] | 223 [160, 337] | 0.01 |
| Index PCI vessels | |||
| Left anterior descending artery | 36.6% (60/164) | 40.8% (1394/3413) | 0.28 |
| Left circumflex artery | 15.2% (25/164) | 15.9% (541/3413) | 0.84 |
| Right coronary artery | 44.5% (73/164) | 41.8% (1427/3413) | 0.49 |
| Left main coronary artery | 0.6% (1/164) | 0.6% (19/3413) | 0.61 |
| Saphenous vein graft | 3.0% (5/164) | 0.9% (30/3413) | 0.02 |
| TIMI flow (core laboratory analysis) | |||
| TIMI 0/1 flow before PCI | 73.2% (120/164) | 65.0% (2210/3402) | 0.03 |
| TIMI 3 flow after PCI | 87.2% (143/164) | 91.7% (3125/3407) | 0.04 |
Primary PCI was performed in 96.9% and 92.7% of patients with and without IAE, respectively, p = 0.05. By core laboratory analysis, TIMI grade 3 flow was restored in 87.2% and 91.7% of patients with and without IAE, respectively (p = 0.04). Clinical outcomes according to the presence of preprocedural IAE at 30 days and at 3 years are listed in Table 2 . Patients with IAE before PCI were significantly more likely to die at 30 days and at 3 years and had higher rates of major bleeding, resulting in higher rates of MACEs and net adverse clinical events. The 30-day and 3-year mortality rates according to the individual components of IAE are listed in Table 3 .
| Variable | Any IAE (N = 159) | Others (N = 3443) | p Value |
|---|---|---|---|
| 30 Days | |||
| Net adverse cardiac events | 23.3% (37) | 10.7% (366) | <0.0001 |
| Major adverse cardiac events | 12.0% (19) | 5.2% (179) | 0.0001 |
| Death | 8.8% (14) | 2.3% (79) | <0.0001 |
| Cardiac | 8.2% (13) | 2.1% (71) | <0.0001 |
| Non-Cardiac | 0.6% (1) | 0.2% (8) | 0.30 |
| Bleeding-related | 0.6% (1) | 0.0% (1) | 0.002 |
| Stroke-related | 0.0% (0) | 0.0% (1) | 0.84 |
| Reinfarction | 1.9% (3) | 1.9% (63) | 0.88 |
| Q-wave | 1.9% (3) | 1.3% (45) | 0.47 |
| Death or reinfarction | 10.7% (17) | 3.8% (132) | <0.0001 |
| Stroke | 0.7% (1) | 0.7% (25) | 0.93 |
| Target vessel revascularization | 2.0% (3) | 2.4% (82) | 0.75 |
| Stent thrombosis (definite or probable) | 3.5% (5) | 2.3% (71) | 0.37 |
| TIMI major bleeding | 9.2% (14) | 4.0% (138) | 0.002 |
| 3 Years | |||
| Net adverse cardiac events | 38.7% (60) | 26.0% (867) | <0.0001 |
| Major adverse cardiac events | 33.4% (51) | 21.3% (705) | 0.0001 |
| Death | 17.0% (26) | 6.3% (210) | <0.0001 |
| Cardiac | 9.0% (14) | 3.7% (124) | 0.0003 |
| Non-cardiac | 8.8% (12) | 2.7% (86) | <0.0001 |
| Bleeding-related | 0.6% (1) | 0.1% (3) | 0.03 |
| Stroke-related | 0.0% (0) | 0.2% (6) | 0.62 |
| Reinfarction | 8.0% (11) | 7.2% (229) | 0.65 |
| Q-wave | 4.9% (7) | 3.5% (114) | 0.33 |
| Death or reinfarction | 24.2% (37) | 12.4% (410) | <0.0001 |
| Stroke | 1.4% (2) | 1.9% (61) | 0.72 |
| Target vessel revascularization | 14.8% (20) | 13.8% (440) | 0.71 |
| Stent thrombosis (definite or probable) | 5.8% (8) | 5.0% (148) | 0.60 |
| TIMI major bleeding | 10.6% (16) | 4.8% (163) | 0.001 |
| Variable | Mortality | |
|---|---|---|
| 1 month | 36 month | |
| No pre-procedural instability or adverse events (n = 3,433) | 2.3% | 6.3% |
| Any pre-procedural instability or adverse events (n = 159) | 8.8% | 17.0% |
| Hypotension requiring intravenous pressors or IABP (n = 45) | 15.65% | 29.1% |
| Sustained ventricular tachycardia or fibrillation requiring defibrillation or cardioversion (n = 72) | 4.2% | 13.1% |
| Atrial fibrillation or supraventricular tachycardia requiring cardioversion (n = 6) | 0% | 0% |
| Heart block or bradycardia requiring pacemaker (n = 38) | 13.2% | 16.6% |
| Respiratory failure requiring mechanical ventilation (n = 10) | 50.0% | 50.0% |
| Cardiopulmonary resuscitation (n = 23) | 17.4% | 26.1% |
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