Pre–percutaneous coronary intervention (PCI) Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow has been identified as a predictor of final TIMI grade 3 flow and better survival. Yet pharmacologic strategies increasing the rates of pre-PCI TIMI grade 3 flow resulted in more bleeding, without a benefit in survival. The aim of this study was to identify the predictors and implications of spontaneous reperfusion before primary PCI in patients with ST-segment elevation myocardial infarction. The Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) and Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trials were combined, and the predictors of core laboratory–determined baseline TIMI grade 3 flow and 1-year outcomes were analyzed according to baseline TIMI flow. Baseline TIMI grade 3 flow was present in 932 of 5,332 patients (17.5%). The independent predictors of baseline TIMI grade 3 flow were diabetes, longer delay to PCI, smoking, and more extensive coronary disease. Patients with compared to those without baseline TIMI grade 3 flow had significantly higher rates of post-PCI TIMI grade 3 flow (99.1% vs 91.4%, p <0.0001) and lower 1-year all-cause mortality (2.7% vs 4.3%, p = 0.02). By multivariate analysis, baseline TIMI grade 3 flow (hazard ratio 1.65, 95% confidence interval 1.01 to 2.71, p = 0.046) and final TIMI grade 3 flow (hazard ratio 3.67, 95% confidence interval 2.45 to 5.48, p <0.001) were significant independent predictors of 1-year survival. In conclusion, TIMI grade 3 flow is present in about 1 in every 6 patients before PCI and paradoxically is more common in patients with higher risk characteristics. TIMI grade 3 flow before as well as after PCI is an independent predictor of greater 1-year survival. These data should inform future trials of ST-segment elevation myocardial infarction with respect to improvement in outcomes.
Previous studies examining the predictors and implications of baseline Thrombolysis In Myocardial Infarction (TIMI) flow in the infarct-related artery (IRA) in patients with ST-segment elevation myocardial infarction (STEMI) have been limited by modest sample sizes. We therefore combined the databases of 2 of the largest primary percutaneous coronary intervention (PCI) trials performed to date (the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications [CADILLAC] and the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI] trials) to identify the clinical predictors of TIMI grade 3 flow before primary PCI and to revisit its relation with clinical outcomes.
Methods
The CADILLAC and HORIZONS-AMI trials have been previously described in detail. In brief, in the CADILLAC trial, 2,082 patients (angiographic data were evaluable in 2,051) presenting with STEMI within 12 hours of symptom onset were randomized after initial angiography in a 2 × 2 factorial design to balloon angioplasty with or without abciximab or to bare-metal stent implantation with or without abciximab. Primary PCI was performed in all patients. In the HORIZONS-AMI trial, 3,602 patients presenting with STEMI within 12 hours of symptom onset were randomized before angiography to bivalirudin or heparin and a glycoprotein IIb/IIIa inhibitor (1:1 ratio). Angiographic data for PCI patients were evaluable in 3,281. A total of 3,006 patients suitable for stenting were then randomized again to drug-eluting stents or identical bare-metal stents (3:1 ratio). Independent adjudication of clinical events and angiographic core laboratory analysis for the 2 studies were performed at the Cardiovascular Research Foundation in New York, New York, using the same definitions and methods for the 2 studies. The 2 data sets were combined for the purpose of this analysis. End points for the present study included the 30-day and 1-year rates of major adverse cardiac events, defined as death (all-cause and cardiac), reinfarction, stroke, or ischemia-driven target vessel revascularization. We also analyzed the incidence of stent thrombosis, according to Academic Research Consortium definitions. TIMI flow rates were analyzed using standard definitions. Outcomes were then analyzed according to the presence or absence of TIMI grade 3 flow in the IRA at initial angiography.
Continuous and categorical variables are presented as medians with interquartile ranges and as proportions, respectively. Multivariate stepwise regression (entry and exit criteria set at 0.10 for the univariate comparison) was performed to identify predictors of TIMI grade 3 flow. The candidate variables were age, male gender, diabetes mellitus, current smoking, body mass index, hypertension, hyperlipidemia, previous bypass surgery (coronary artery bypass grafting), previous myocardial infarction, previous PCI, Killip class 2 to 4 heart failure, history of peripheral vascular disease, history of congestive heart failure, left anterior descending coronary artery (LAD) IRA versus non-LAD IRA, number of diseased vessels, door-to-balloon time (hours), and creatinine clearance ≤60 versus >60 ml/min/1.73 m 2 . The left ventricular ejection fraction was not considered, because of a lack of data in a nearly 25% of patients. Cox proportional-hazards multivariate regression analysis was performed to identify whether baseline TIMI grade 3 flow was an independent predictor of 1-year total (n = 187) and cardiac (n = 119) mortality, using the variables listed in Tables 1 to 3 , first without including final TIMI flow and then adding it to the model. The multivariate model for cardiac mortality included only the following variables known or presumed to influence outcome: baseline TIMI grade 0 to 2 flow, final TIMI grade 0 to 2 flow, creatinine clearance ≤60 ml/min/1.73 m 2 , age, diabetes, body mass index, the left ventricular ejection fraction, Killip class 2 to 4 heart failure, history of congestive heart failure, LAD versus non-LAD IRA, and number of diseased vessels. A p value <0.05 was considered statistically significant. All analyses were performed using SAS version 9.2 (Cary, North Carolina).
| Baseline TIMI Grade 3 Flow | Baseline TIMI Grade 0–2 Flow | ||
|---|---|---|---|
| Variable | (n = 932) | (n = 4,400) | p Value |
| United States site | 53.3% (497/932) | 42.9% (1,886/4,400) | <0.0001 |
| Non-United States site | 46.7% (435/932) | 57.1% (2,514/4,400) | |
| Age (years) | 60 (51–70) | 60 (52–69) | 0.36 |
| Men | 72.9% (679/932) | 76.2% (3,352/4,400) | 0.03 |
| Caucasian | 93.7% (449/479) | 94.4% (2,644/2,802) | 0.59 |
| Height (cm) | 172 (165–178) | 173 (166–178) | 0.01 |
| Weight (kg) | 80 (70–91) | 81 (72–91) | 0.08 |
| Body mass index (kg/m 2 ) | 27 (24–30) | 27 (25–30) | 0.31 |
| Hypertension (history) | 53.2% (495/931) | 50.2% (2,207/4,400) | 0.10 |
| Hyperlipidemia (history) | 41.6% (387/931) | 40.7% (1,792/4,400) | 0.63 |
| Current smoker | 48.7% (452/929) | 45.0% (1,976/4,387) | 0.05 |
| Diabetes mellitus | 20.6% (192/931) | 15.5% (680/4,400) | 0.0002 |
| Medically treated | 16.3% (152/931) | 12.6% (552/4,400) | 0.002 |
| Insulin treated | 6.3% (59/931) | 3.7% (164/4,400) | 0.0006 |
| Previous infarct | 14.5% (135/930) | 11.2% (491/4,400) | 0.005 |
| Previous PCI | 12.7% (118/931) | 10.3% (455/4,399) | 0.04 |
| Previous bypass surgery | 3.2% (30/931) | 2.2% (95/4,400) | 0.06 |
| Previous heart failure | 1.5% (14/931) | 1.7% (74/4,400) | 0.78 |
| Peripheral vascular disease | 5.4% (50/931) | 3.4% (150/4,399) | 0.006 |
| Killip class | |||
| 1 | 90.8% (844/930) | 90.4% (3,964/4,383) | 0.81 |
| 2 | 8.1% (75/930) | 8.5% (373/4,383) | 0.70 |
| 3 | 0.9% (8/930) | 0.5% (24/4,383) | 0.25 |
| 4 | 0.6% (3/478) | 0.8% (22/2,799) | 1.00 |
| ST-segment elevation or left bundle branch block | 79.2% (331/418) | 90.4% (1,374/1,520) | <0.0001 |
| Non-ST-segment elevation | 20.8% (87/418) | 9.6% (146/1,520) | <0.0001 |
| Ejection fraction (%) | 55 (45–60) | 50 (40–55) | <0.0001 |
| Number of narrowed vessels | 1.3 ± 0.6 | 1.3 ± 0.6 | 0.002 |
| 1 | 73.3% (679/926) | 78.3% (3,415/4,364) | 0.001 |
| 2 | 18.5% (171/926) | 15.9% (695/4,364) | 0.06 |
| 3 | 8.0% (74/926) | 5.8% (253/4,364) | 0.02 |
| Serum creatinine (mg/dl) | 1.0 ± 0.3 | 1.0 ± 0.4 | 0.10 |
| Creatinine clearance (ml/min/1.73 m 2 ) | 89 (68–113) | 88 (68–113) | 0.67 |
| TIMI Grade 3 Flow | TIMI Grade 0–2 Flow | ||
|---|---|---|---|
| Variable | (n = 932) | (n = 4,400) | p Value |
| Symptom onset to first hospital (minutes) | 106 (60–180) | 115 (65–206) | 0.03 |
| Symptom onset to study hospital (minutes) | 120 (65–210) | 120 (69–225) | 0.26 |
| Door-to-balloon (minutes) ⁎ | 122 (92–167) | 103 (76–142) | <0.0001 |
| Symptom onset to first balloon inflation (minutes) | 240 (174–352) | 225 (164–344) | 0.006 |
| TIMI Grade 3 Flow | TIMI Grade 0–2 Flow | ||
|---|---|---|---|
| Variable | (n = 932) | (n = 4,400) | p Value |
| Index PCI vessel | |||
| LAD | 38.6% (360/932) | 41.0% (1,806/4,400) | 0.17 |
| Left circumflex | 19.1% (178/932) | 16.5% (725/4,400) | 0.05 |
| Right | 44.8% (418/932) | 45.4% (1,996/4,400) | 0.78 |
| Left main | 0.6% (6/932) | 0.3% (14/4,400) | 0.14 |
| Vein graft | 0.6% (3/479) | 1.1% (32/2,802) | 0.47 |
| Initial TIMI flow grade | |||
| 0/1 | 0.0% (0/932) | 83.3% (3,667/4,400) | <0.0001 |
| 2 | 0.0% (0/932) | 16.7% (733/4,400) | <0.0001 |
| 3 | 100.0% (932/932) | 0.0% (0/4,400) | NA |
| Final TIMI flow grade | |||
| 0/1 | 0.2% (2/932) | 2.4% (104/4,396) | <0.0001 |
| 2 | 0.5% (5/932) | 6.2% (271/4,396) | <0.0001 |
| 3 | 99.1% (924/932) | 91.4% (4,020/4,396) | <0.0001 |
Results
Core laboratory angiographic data were evaluated in 5,332 patients in whom PCI was performed in CADILLAC (n = 2,051) and HORIZONS-AMI (n = 3,281). At baseline angiography, TIMI grade 3 flow in the IRA was present in 932 patients (17.5%), while TIMI grade 0 to 2 flow was present in 4,400 patients (82.5%), including 733 (16.7%) with TIMI grade 2 flow and 3,667 (83.5%) with TIMI grade 0 or 1 flow. The baseline characteristics of the 2 groups are listed in Table 1 . Patients with TIMI grade 3 flow had, in general, higher risk features than those with TIMI grade 0 to 2 flow, except for a lower rate of ST-segment elevation. Important periprocedural aspects are listed in Tables 2 and 3 . Patients with TIMI grade 3 flow had significantly longer intervals from symptom onset to first device activation and from hospital arrival to first device activation than those with TIMI grade 0 to 2 flow, although these differences amounted to only 15 to 20 minutes. Final TIMI grade 3 flow was achieved significantly more often in those with baseline TIMI grade 3 flow (99.1% vs 91.4%, p <0.001).
Overall, the multivariate regression model had modest predictability for TIMI grade 3 flow (area under the curve 0.61). The independent predictors of TIMI grade 3 flow were diabetes mellitus (odds ratio [OR] 1.39, 95% confidence interval [CI] 1.13 to 1.71, p = 0.002), current smoking (OR 1.37, 95% CI 1.15 to 1.61, p <0.001), extent of coronary artery disease (OR 1.16, 95% CI 1.01 to 1.32 per vessel, p = 0.03), and longer door-to-device time (OR 1.26, 95% CI 1.19 to 1.34 per hour, p <0.001). Similar results were obtained for the independent predictors of baseline TIMI grade 2 or 3 flow, with the exception of male gender, which was weakly associated with TIMI grade 2 or 3 flow (OR 0.85, 95% CI 0.73 to 1.00, p = 0.04).
Independently adjudicated events at 30 days and 1 year are listed in Tables 4 and 5 , respectively. There were no significant differences in major adverse cardiac events or bleeding events at 30 days between patients with TIMI grade 3 flow and those with TIMI grade 0 to 2 flow at baseline angiography. By 1 year, however, patients with initial TIMI grade 3 flow had lower rates of all-cause mortality (2.7% vs 4.3%, p = 0.02, Kaplan-Meier analysis; Figure 1 ) and cardiac mortality (1.3% vs 2.9%, p = 0.04). Ischemia-driven target vessel revascularization occurred more frequently in patients with initial TIMI grade 3 flow at 1 year (11.3% vs 8.8%, p = 0.02). There were no significant differences in the rates of reinfarction, stent thrombosis, or bleeding between the 2 groups at any time point. Similar results were obtained when baseline flow was tabulated as TIMI grade 2 or 3 versus TIMI grade 0 or 1, with the exception of need for revascularization, which was no longer significantly different among the groups.
