Differential Clinical Impact of Angiographic Mechanisms Underlying Periprocedural Myocardial Infarction After Drug-Eluting Stent Implantation Duk-Woo Park, MD, PhD Division of Cardiology, University of Ulsan College of Medicine Heart Institute, Asan Medical Center, Seoul, Korea

Disclosure Statement of Financial Interest Research funds from the CardioVascular Research Foundation (CVRF), Seoul, Korea and a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Korea (A102065). No industry sponsorship

Background Periprocedural myocardial infarction (MI) is the most common complication after PCI. The incidence of periprocedural MI varies from 5% to 30%, which can range from a minor elevation of cardiac enzymes to a large-sized infarct. The detrimental effect of periprocedural MI on survival according to the levels of enzyme elevation has been well documented.

Background PCI-related MI may result from angiographically recognizable complications or angiographically non- visible mechanisms. Limited data are available on the relative frequency and angiographic patterns of the mechanisms underlying periprocedural MI and whether there are substantial differences in prognostic relevance according to these angiographic mechanisms.

Purpose Our study was to investigate the angiographic mechanisms of periprocedural MI using a core lab. and to evaluate the different effects of periprocedural MI on mortality among patients receiving drug-eluting stent (DES). To accomplish this, we pooled and analyzed data from available RCTs or registries designed with similar methods including case report forms, definitions and adjudication procedures.

Database Databases from 10 independent, prospective clinical studies (8 RCT and 2 registry), in which enrolled patients were treated with DES for stable CAD or ACS. All of the studies used uniform endpoint definitions, adjudication processes, and follow-up procedures. All databases were maintained at the Clinical Research Center of the Asan Medical Center, Seoul, Korea, and a convenience sample of 10 clinical studies was available in existing merged data sets.

PCI and Cardiac Enzyme Measurement All studies of patients undergoing PCI in whom periprocedural CK-MB data and mortality data were prospectively collected. Blood was routinely collected for the measurement of CK an CK-MB before stenting, every 8 hours for the first 24 hours after the procedure, and daily thereafter during hospitalization. Routine measurement of cardiac troponin after PCI was not performed in each center due to no reimbursement of the government for troponin measurements in PCI situations.

Periprocedural MI Definition The occurrence of MI was assessed according to the universal definition of MI. MI related to procedure was defined as either an (1) increase in CK-MB at least 3 times the upper limit of normal and (2) at least 50% greater than the most recent pre- procedure concentration; for NSTEMI/STEMI patients, peak CK-MB > 1.5 x previous trough with falling or normal CK-MB.

MI Events Adjudication and Classification All of the studies utilized the same angiographic core lab. After evaluation of baseline and postprocedural CAG, angiographic mechanisms of MI were recorded as one of the following: - side-branch occlusion, - slow flow or no-reflow, - distal embolization, - thrombus, - flow-limiting dissection, - disruption of collateral flow, - others, - non-identifiable mechanical causes. Type 1 (MI d/t SB obstruction) Type 2 (MI d/t other angiographic complications) Type 3 (MI without angiographically identifiable causes

Clinical Follow-Up Among studies, clinical follow-up was performed via office visit or telephone contact at 1, 6, and 12 months and then every 6 or 12 months thereafter according to the study protocol. For validation of complete follow-up data, information about vital status was obtained from the National Population Registry of the Korea National Statistical Office with the use of a unique personal identification number.

Statistical Analysis Baseline characteristics were compared among groups without periprocedural MI and with different types of periprocedural MI by ANOVA and the χ 2 test. Survival curves for between-groups comparisons was created using the K-M method and compared by the log-rank test. Univariate and multivariable Cox proportional- hazards regression models were used to estimate the effect of different types of periprocedural MI on mortality with reference to non-periprocedural MI.

RESULTS

Summary of Merged Clinical Studies SourceNo. Multi- centerRCT Type of Patients or Lesions EvaluatedDES Used 1. ZEST2645OOAll-comer PCI patientsZES vs. SES vs. PES 2. ZEST-AMI328OOSTEMIZES vs. SES vs. PES 3. LONG-DES II500OOLong (> or =25 mm)SES vs. PES 4. LONG-DES III450OOLong (> or =25 mm)EES vs. SES 5. LONG-DES IV500OOLong (> or =25 mm)ZES vs. SES 6. ESSENCE-DM300OODiabetic patientsEES vs. SES 7. DECLARE-LONG II499OOLong (> or =25 mm)ZES 8. REAL-LATE1625OOAll-comer PCI patientsSES, PES, ZES, EES 9. ASAN-VERIFY3370XXAll-comer PCI patientsSES, PES, ZES, EES 10. IRIS-DES6166OXAll-comer PCI patientsEES vs. SES Total16383

Angiographic Mechanisms of Peri-MI Underlying CausesNo. (%) Type 1 Side-branch occlusions690 (59.9) Type 2 (other angiographic mechanisms)223 (19.4) Slow- or no-reflow (abrupt closure)93 (8.1) Distal embolization35 (3.0) Thrombus43 (3.7) Flow-limiting dissection42 (3.6) Disruption of collateral flow1 (0.1) Others9 (0.8) Type 3 Non-identifiable mechanical causes238 (20.7) Incidence of Periprocedural MI: 7.0% (1,151 / 16,383)

Relative Percent (%) AllType 1Type 2Type 3 CK-MB ratio: 3 to 10 Relative Proportions of CK-MB Levels According to the Types of Angiographic Mechanisms

Baseline Clinical Characteristics N (%) Variable No MI (N=15232) Type 1 (N=690) Type 2 (N=223) Type 3 (N=238)P Value Age ― yr62.4± ± ± ±10.0<0.001 Men10578 (69.5)420 (60.9)151 (67.7)143 (60.1)<0.001 BMI, kg/m ± ± ± ± Diabetes4926 (32.3)232 (33.6)68 (30.5)69 (29.0)0.56 Hypertension9074 (59.6)473 (68.6)127 (57.0)154 (64.7)<0.001 Current smoker4373 (28.7)154 (22.3)55 (24.7)67 (28.2)0.002 Hyperlipidemia6930 (45.5)357 (51.7)129 (57.9)108 (45.4)<0.001

Baseline Clinical Characteristics N (%) Variable No MI (N=15232) Type 1 (N=690) Type 2 (N=223) Type 3 (N=238)P Value Previous MI777 (5.1)26 (3.8)10 (4.5)10 (4.2)0.40 Previous PCI2174 (14.3)80 (11.6)33 (14.8)27 (11.3)0.14 Previous CABG295 (1.9)11 (1.6)2 (0.9)1 (0.4)0.25 Previous CHF234 (1.5)11 (1.6)3 (1.4)5 (2.1)0.83 Previous stroke907 (6.0)47 (6.8)14 (6.3)22 (9.2)0.15 PVD227 (1.5)13 (1.9)6 (2.7)4 (1.7)0.33 Chronic lung disease255 (1.7)11 (1.6)7 (3.1)5 (2.1)0.32 Renal insufficiency315 (2.1)22 (3.2)4 (1.8)9 (3.8)0.07 ACS8526 (56.0)319 (46.2)105 (47.1)127 (53.4)<0.001 EF (%)59.2± ± ± ±

Baseline Lesion Characteristics N (%) Variable No MI (N=15232) Type 1 (N=690) Type 2 (N=223) Type 3 (N=238)P Value Multivessel disease7681 (50.4)492 (71.3)153 (68.6)157 (66.0)<0.001 LAD disease9513 (62.5)514 (74.5)154 (69.1)168 (70.6)<0.001 Left main disease843 (5.5)80 (11.6)21 (9.4)23 (9.7)<0.001 Bifurcation lesion3900 (25.6)306 (44.4)91 (40.8)91 (38.2)<0.001 Long lesion (>20 mm)10925 (71.7)631 (91.5)198 (88.8)206 (86.6)<0.001 Total occlusion2309 (15.2)49 (7.1)46 (20.6)31 (13.0)<0.001

Baseline Procedural Characteristics N (%) Variable No MI (N=15232) Type 1 (N=690) Type 2 (N=223) Type 3 (N=238)P Value DES subtype<0.001 Sirolimus6886 (45.2)304 (44.1)106 (47.5)98 (41.2)<0.001 Paclitaxel1874 (12.3)69 (10.0)15 (6.7)20 (8.4) Zotarolimus2160 (14.2)79 (11.5)32 (14.4)22 (9.2) Everolimus3591 (23.6)204 (29.6)59 (26.5)85 (35.7) Resolute zotarolimus473 (3.1)30 (4.4)8 (3.6)11 (4.6) Others248 (1.6)4 (0.6)3 (1.4)2 (0.8) No. of stents1.7±1.02.7±1.32.5±1.32.3±1.2<0.001 Total stent length, mm42.3± ± ± ±32.9<0.001 Guidance of IVUS9269 (60.9)510 (73.9)160 (71.8)152 (63.9)<0.001 Use of Gp IIb/IIIa inhibitor3668 (24.1)121 (17.5)66 (29.6)48 (20.2)<0.001 Use of cilostazol3950 (25.9)212 (30.7)64 (28.7)65 (27.3)0.03

K-M Curves According to Types of Periprocedural MI

Incidence Rates, Unadjusted and Adjusted HR for Mortality, According to the Type of Periprocedural MI UnadjustedAdjusted† Outcome Total No. and 2-year rate of events HR (95% CI)P HR (95% CI)P No Peri-MI (N=15232)307 (2.0%)Referent Peri-MI (N=1151)37 (3.6%) 1.76 (1.24–2.48) (1.08–1.89) 0.01 Type 1 (N=690)16 (2.8%) 1.27 (0.79–2.06) (0.67–1.73) 0.77 Type 2 (N=223)13 (6.1%) 3.06 (1.57–5.96) (1.57–4.63) Type 3 (N=238)8 (3.2%) 1.87 (1.08–3.23) (0.94–1.72) 0.12 †Adjusted for study, age, sex, BMI, DM, HTN, smoking, hyperlipidemia, history of MI, PCI, or stroke, chronic lung disease, renal insufficiency, ACS, EF, MVD, LM disease, bifurcation, total occlusion, DES type, total number of stents, and use of Gp IIb/IIIa inhibitor.

Conclusion Among patients who underwent PCI with DES, periprocedural MI was associated with an increased risk of mortality. There were substantial differences in mortality depending on the different angiographic mechanisms of periprocedural MI, showing that MI due to complicated angiographic causes was related with increased mortality, whereas MI due to side-branch occlusion or without identifiable angiographic causes did not affect mortality.

Clinical Implication The 3 rd definition of MI adopted a ≥5 enzyme elevations and considered angiographic evidence of flow-limiting complications (such as loss of SB occlusion, slow flow or no-reflow, or embolization) as diagnostic criteria. However, the clinical impact of angiographic mechanisms of periprocedural MI is still unknown. The overall findings of our study highlight the need for further research to determine the diagnostic and prognostic value of angiographic mechanisms, when defining periprocedural MI, and to inform optimal management of these complications.