Periprocedural myocardial infarction (MI) can be induced by several angiographic mechanisms. However, there are limited data on whether these mechanisms differentially affect clinical outcomes. The purpose of our study was to investigate the impact of periprocedural MI on mortality according to the underlying angiographic mechanisms after drug-eluting stent (DES) implantation. We pooled the databases from 7 coronary stent trials using DES. Periprocedural MI was classified according to its underlying angiographic mechanisms as type 1 (due to side-branch occlusion), type 2 (due to other angiographic complications), or type 3 (without angiographically identifiable causes). Among 10,889 patients treated with DES, 768 (7.1%) experienced periprocedural MI; 463 cases (60.3%) were driven by type 1 cause, 138 (18.0%) by type 2 cause, and 167 (21.7%) by type 3 cause. Mortality rates at 2 years were higher in patients with periprocedural MI than in those without (3.5% vs 2.1%, respectively). Significant differences in mortality were observed according to the angiographic mechanisms of MI (type 1: 2.8% vs type 2: 6.1% vs type 3: 3.1%). After multivariable adjustment, type 2 MI was significantly associated with an increased risk of mortality (hazard ratio 2.65, 95% confidence interval 1.77 to 3.96), whereas type 1 and type 3 MI were not related with increased mortality. In conclusion, among patients receiving DES implantation, periprocedural MI was associated with increased mortality, and there were differential associations with mortality according to the underlying angiographic mechanisms.
The purpose of the present study was to investigate the angiographic mechanisms of periprocedural myocardial infarction (MI) using a core laboratory angiographic analysis and to evaluate the different effects of periprocedural MI on mortality according to the mechanisms of procedural infarction among patients who underwent percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation. To accomplish this, we pooled and analyzed data from several clinical studies with similar methods, including case report forms, definitions, and adjudication process.
Methods
For the present analysis, databases from 7 independent, prospective clinical studies (6 randomized clinical trials and 1 observational study), in which enrolled patients had undergone PCI with DES for the treatment of stable coronary artery disease or acute coronary syndromes, were pooled to provide a patient-level data analysis. The details of the study designs and primary results have been previously published elsewhere, and justification for pooling has been previously reported. These studies contain information on patient demographics, cardiac or coexisting risk factors, clinical manifestations, left ventricular function, angiographic and procedural characteristics, and clinical outcomes. The primary clinical outcome of this study was cumulative all-cause mortality. For validation of complete follow-up data on mortality, information on deaths from the hospital was matched with the records from the National Population Registry of the Korea National Statistical Office using a unique personal identification number. All the studies were approved by the local institutional review board, and all patients provided written informed consent.
Routine measurements of creatine kinase-MB (CK-MB) isoenzyme by mass assay were performed in all patients according to each study protocol. Blood samples were routinely collected for the measurement of CK-MB levels at baseline, every 8 hours for the first 24 hours after the procedure and daily thereafter during hospitalization. For each patient, the CK-MB ratio was calculated as the ratio between the peak CK-MB level and the upper limit of normal for the participating laboratory of each study. Among these studies, routine measurement of cardiac troponin after PCI was not available.
For all studies included in this analysis, all CK-MB elevations were reviewed by an independent clinical events committee, classifying MIs according to the predefined criteria. Periprocedural MI was defined as an elevation of CK-MB >3 times the upper limit of the normal range in at least 2 blood samples with a normal baseline value within 48 hours after the procedure. In patients with pre-PCI values higher than the upper normal limits, a CK-MB re-elevation at least 50% greater than the most recent preprocedure concentration was required with documentation that biomarkers were decreasing or at nadir before PCI. All the studies utilized the same angiographic core laboratory (Asan Medical Center, Seoul, Korea). For periprocedural MI events, angiographic mechanisms of MI were recorded as one of the following (as prespecified in the event adjudication form): side-branch occlusion, slow flow or no-reflow (abrupt closure), distal embolization, thrombus, flow-limiting dissection, disruption of collateral flow, others, or nonidentifiable mechanical causes. For the current analysis, according to the underlying angiographic mechanisms, MI was classified into 1 of the 3 types: type 1, MI due to side-branch occlusion; type 2, MI due to other angiographic complications (e.g., slow flow or no-reflow, distal embolization, thrombus, flow-limiting dissection, disruption of collateral flow, or others); type 3, MI without angiographically identifiable causes. A similar classification scheme was suggested in previous study.
Continuous variables are described as mean and SD, and categorical variables are described as counts and percentages. Baseline clinical, angiographic, and procedural characteristics were compared among groups without periprocedural MI and with different types of periprocedural MI using the analysis of variance for continuous variables and the chi-square or Fisher’s exact test for categorical variables, as appropriate. Cumulative mortality rates and survival curves between groups were constructed from Kaplan-Meier estimates and compared by the use of the log-rank test. Cox proportional hazards regression models were used to estimate the effect of different types of periprocedural MI on mortality with reference to nonperiprocedural MI. To account for between-study heterogeneity and within-study clustering, because patients at the same study may have similar profiles of characteristics, p values and confidence intervals were calculated using robust standard errors based on sandwich estimators. After unadjusted analyses were initially performed, multivariable Cox proportional hazards regression modeling was performed to adjust potentially confounding factors, which were significantly associated with outcomes (p <0.05) or clinically relevant irrespective of their statistical significance. The following variables were entered into the final multivariable models: study, age, sex, body-mass index, diabetes, previous MI, renal insufficiency, acute coronary syndrome, ejection fraction, multivessel disease, left main disease, bifurcation lesion, total occlusion, DES type, total number of stents, and use of glycoprotein IIb/IIIa inhibitor. All reported p values were two sided, and p values of <0.05 were considered to indicate statistical significance. SAS software, version 9.1 (SAS Institute, Cary, North Carolina) was used for all statistical analyses.
Results
A total of 10,889 patients from 7 PCI studies using DES were included in this analysis. The number of patients enrolled in each study, the types of study design, the types of patients or lesions evaluated, and the type of DES compared are listed in Table 1 . Among them, 768 (7.1%) patients sustained a periprocedural MI. After source documentation of MI with a detailed angiographic review at baseline and postprocedure, the angiographic mechanisms underlying periprocedural MI were listed in Table 2 . Of the 768 patients with a periprocedural MI, 463 cases (60.3%) were driven by side-branch occlusion (type 1), 138 (18.0%) by other angiographic complications (type 2), and 167 (21.7%) had no identifiable angiographic causes (type 3). Among 768 patients with a periprocedural MI, 324 (42.2%) had mild CK-MB elevation (3 to <5 ratio), 249 (32.4%) had moderate CK-MB elevation (5 to <10 ratio), and 195 (25.4%) had large CK-MB elevation (>10 ratio). Figure 1 shows the significant differences in the levels of cardiac enzyme elevation according to the type of MI. The proportion of large infarct with a CK-MB ratio >10 was higher in patients with type 2 MI rather than in those with type 1 and type 3 MI (37.7% vs 26.8% and 11.4%, respectively).
| Source | No. of Patients Enrolled | Types of Study Design | Type of Patients or Lesions Evaluated | DESs Compared | |
|---|---|---|---|---|---|
| Multicenter | Randomized | ||||
| ZEST | 2,645 | O | O | All-comer patients with PCI | Zotarolimus vs sirolimus vs paclitaxel eluting |
| ZEST-AMI | 328 | O | O | STEMI | Zotarolimus vs sirolimus vs paclitaxel eluting |
| LONG-DES II | 500 | O | O | Long (≥25 mm) native coronary lesions | Sirolimus vs paclitaxel eluting |
| LONG-DES III | 450 | O | O | Long (≥25 mm) native coronary lesions | Everolimus vs sirolimus eluting |
| LONG-DES IV | 500 | O | O | Long (≥25 mm) native coronary lesions | Zotarolimus vs rolimus eluting |
| ESSENCE-Diabetes | 300 | O | O | Patients with diabetes | Everolimus vs sirolimus eluting |
| IRIS-DES | 6,166 | O | X | All-comer patients with PCI | Everolimus vs sirolimus eluting |
| Underlying Causes | |
|---|---|
| Type 1 | |
| Side-branch occlusion | 463 (60.3) |
| Type 2 (other angiographic complications) | 138 (18.0) |
| Slow flow or no-reflow (abrupt closure) | 59 (7.7) |
| Distal embolization | 23 (3.0) |
| Thrombus | 25 (3.3) |
| Flow-limiting dissection | 26 (3.4) |
| Disruption of collateral flow | 1 (0.1) |
| Others | 4 (0.5) |
| Type 3 | |
| Nonidentifiable mechanical causes | 167 (21.7) |
Baseline clinical characteristics among patients without periprocedural MI and those with different types of periprocedural MI are listed in Table 3 . Compared with patients without periprocedural MI, those with periprocedural MI were older, were more likely to be women, and had lower prevalence of acute coronary syndrome presentations. Detailed data on angiographic and procedural characteristics between groups are listed in Table 4 . Overall, patients who sustained a periprocedural MI had higher risk lesion characteristics such as multivessel disease, left main disease, bifurcation lesion, and long lesion. The number of stents used was significantly higher, and the total stent length was longer in patients with periprocedural MI than in those without periprocedural MI.
| Variable | No MI (n = 10,121) | Type 1 (n = 463) | Type 2 (n = 138) | Type 3 (n = 167) | p Value |
|---|---|---|---|---|---|
| Age (yrs) | 62.7 ± 10.4 | 64.7 ± 9.4 | 64.8 ± 9.7 | 65.6 ± 10.2 | <0.001 |
| Men | 6,876 (67.9) | 275 (59.4) | 89 (64.5) | 97 (58.1) | <0.001 |
| Body-mass index (kg/m 2 ) | 24.8 ± 3.0 | 24.9 ± 3.0 | 24.4 ± 2.9 | 24.5 ± 3.1 | 0.20 |
| Diabetes mellitus | 3,483 (34.4) | 161 (34.8) | 45 (32.6) | 48 (28.7) | 0.46 |
| Hypertension | 6,132 (60.6) | 322 (69.6) | 78 (56.5) | 114 (68.3) | <0.001 |
| Current smoker | 2,910 (28.8) | 108 (23.3) | 31 (22.5) | 51 (30.5) | 0.03 |
| Hypercholesterolemia (total cholesterol >200 mg/dl) | 4,342 (42.9) | 220 (47.5) | 70 (50.7) | 69 (41.3) | 0.06 |
| Previous MI | 509 (5.0) | 19 (4.1) | 5 (3.6) | 8 (4.8) | 0.72 |
| Previous PCI | 1,331 (13.2) | 50 (10.8) | 18 (13.0) | 18 (10.8) | 0.41 |
| Previous coronary artery bypass grafting | 186 (1.8) | 7 (1.5) | 1 (0.7) | 0 | 0.26 |
| Previous congestive heart failure | 179 (1.8) | 10 (2.2) | 2 (1.5) | 5 (3.0) | 0.52 |
| Previous stroke | 690 (6.8) | 29 (6.3) | 9 (6.5) | 14 (8.4) | 0.83 |
| Peripheral vascular disease | 135 (1.3) | 3 (0.7) | 3 (2.2) | 1 (0.6) | 0.39 |
| Chronic lung disease | 240 (2.4) | 11 (2.4) | 7 (5.1) | 5 (3.0) | 0.21 |
| Renal insufficiency | 245 (2.4) | 17 (3.7) | 3 (2.2) | 8 (4.8) | 0.08 |
| Acute coronary syndrome | 5,705 (56.4) | 222 (48.0) | 73 (52.9) | 96 (57.5) | 0.004 |
| Ejection fraction (%) | 59.5 ± 9.2 | 59.7 ± 8.3 | 57.5 ± 10.8 | 60.0 ± 9.8 | 0.06 |
| Variable | No MI (n = 10,121) | Type 1 (n = 463) | Type 2 (n = 138) | Type 3 (n = 167) | p Value |
|---|---|---|---|---|---|
| Multivessel coronary disease | 5,095 (50.3) | 332 (71.7) | 92 (66.7) | 108 (64.7) | <0.001 |
| Left anterior descending | 6,225 (61.5) | 315 (68.0) | 90 (65.2) | 115 (68.9) | 0.007 |
| Left main | 389 (3.8) | 41 (8.9) | 9 (6.5) | 13 (7.8) | <0.001 |
| Bifurcation lesion | 2,546 (25.2) | 195 (42.1) | 52 (37.7) | 64 (38.3) | <0.001 |
| Long lesion (>20 mm) | 7,263 (71.8) | 419 (90.5) | 120 (87.0) | 137 (82.0) | <0.001 |
| Total occlusion | 1,364 (13.5) | 25 (5.4) | 22 (15.9) | 18 (10.8) | <0.001 |
| DES subtype | <0.001 | ||||
| Sirolimus | 4,596 (45.4) | 215 (46.4) | 67 (48.6) | 72 (43.1) | |
| Paclitaxel | 1,170 (11.6) | 48 (10.4) | 11 (8.0) | 15 (9.0) | |
| Zotarolimus | 952 (9.4) | 23 (5.0) | 13 (9.4) | 3 (1.8) | |
| Everolimus | 3,185 (31.5) | 157 (33.9) | 44 (31.9) | 68 (40.7) | |
| Resolute zotarolimus | 218 (2.2) | 20 (4.3) | 3 (2.2) | 9 (5.4) | |
| No. of stents | <0.001 | ||||
| 1 | 5,571 (55.0) | 95 (20.5) | 36 (26.1) | 61 (36.5) | |
| 2 | 2,730 (27.0) | 146 (31.5) | 46 (33.3) | 46 (27.5) | |
| ≥3 | 1,820 (18.0) | 222 (48.0) | 56 (40.6) | 60 (35.9) | |
| Mean | 1.7 ± 1.0 | 2.6 ± 1.3 | 2.5 ± 1.4 | 2.2 ± 1.2 | <0.001 |
| Total stent length (mm) | <0.001 | ||||
| <10 | 4 (0.1) | 0 | 0 | 0 | |
| 10–19 | 1,853 (18.3) | 31 (6.7) | 11 (8.0) | 24 (14.4) | |
| 20–29 | 2,481 (24.5) | 61 (13.2) | 25 (18.1) | 27 (16.2) | |
| ≥30 | 5,783 (57.1) | 371 (80.1) | 102 (73.9) | 116 (69.5) | |
| Mean | 40.9 ± 25.5 | 58.5 ± 31.8 | 57.4 ± 34.2 | 50.9 ± 31.3 | <0.001 |
| Guidance of intravascular ultrasound | 5,339 (52.8) | 312 (67.4) | 88 (63.8) | 95 (56.9) | <0.001 |
| Use of glycoprotein IIb/IIIa inhibitor | 2,660 (37.2) | 92 (24.3) | 41 (32.8) | 26 (24.1) | <0.001 |
| Use of cilostazol | 5,339 (52.8) | 312 (67.4) | 88 (63.8) | 95 (56.9) | <0.001 |
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