Impact of Preprocedural TIMI Flow on Myocardial Perfusion, Distal Embolization and Mortality in Patients with ST-Segment Elevation Myocardial Infarction Treated by Primary Angioplasty and Glycoprotein IIb/IIIa Inhibitors

Abstract: Background. Despite optimal epicardial recanalization, primary angioplasty for ST-elevation myocardial infarction (STEMI) is still associated with suboptimal reperfusion in a relatively large proportion of patients. The aim of the current study was to evaluate the impact of preprocedural TIMI flow on myocardial perfusion, distal embolization, and survival among STEMI patients undergoing primary angioplasty with glycoprotein (GP) IIb/IIIa inhibitors. Methods. Our population is represented by a total of 1637 patients undergoing primary angioplasty for STEMI treated with GP IIb/IIIa inhibitors. Myocardial perfusion was evaluated by myocardial blush grade and ST-segment resolution. Follow-up data were collected between 30 days and 1 year after primary angioplasty. Results. Poor preprocedural TIMI flow (TIMI 0-1) was observed in 1039 patients (63.5%), and was associated with higher Killip class at presentation (P =.006), longer time-to-treatment (P =.03), less often with early administration of GP IIb/IIIa inhibitors (P <.001), impaired postprocedural epicardial (P =.001) and myocardial perfusion (determined by myocardial blush grade, P <.001 and/or ST-segment resolution (P<.001), and distal embolization (P=.041). At 206 ± 158 days follow-up, poor preprocedural recanalization was associated with a significantly higher mortality (adjusted odds ratio, 0.58; 95% CI, 0.34-0.96; P=.034). Conclusion. This study shows that among patients with STEMI undergoing primary angioplasty with GP IIb/IIIa inhibitors, poor preprocedural TIMI flow is associated with higher incidence of distal embolization and impaired epicardial and myocardial perfusion, and significantly higher mortality. 

J INVASIVE CARDIOL 2012;24(7):324-327

Key words: primary angioplasty, perfusion, preprocedural recanalization, mortality

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Primary angioplasty has been shown to be superior to thrombolysis, mainly due to restoration of TIMI 3 flow in the vast majority of patients.¹ However, epicardial recanalization does not guarantee optimal myocardial reperfusion, and is still unsatisfactory in a large proportion of patients, mainly due to no-reflow phenomenon and distal embolization.^2-4 Time-to-treatment has been shown to be a major determinant of impaired myocardial perfusion and survival among ST-elevation myocardial infarction (STEMI) patients undergoing primary angioplasty.^5-7 Early recanalization may therefore imply a shorter ischemia time and smaller infarct size. So far, no study has investigated the prognostic role of preprocedural TIMI flow among patients treated with glycoprotein (GP) IIb/IIIa inhibitors. In fact, this therapy has been shown to improve perfusion and mortality, and thus may attenuate the deleterious effects of ischemia time. Thus, the aim of the current study was to investigate the impact of preprocedural TIMI flow on myocardial perfusion, distal embolization, and survival among STEMI patients treated with primary angioplasty and GP IIb/IIIa inhibitors.

Methods

Our population is represented by a total of 1637 patients with STEMI treated by primary angioplasty and GP IIb/IIIa inhibitors, included in the EGYPT cooperation. Details have been previously shown.⁸ Informed consent was obtained from each patient to be included in each trial, which were approved by local ethical committees. All patients were admitted within 12 hours of symptom onset. All patients received aspirin (500 mg intravenously) and heparin (5000 to 10000 IU intravenously) before the procedure. All patients were treated with GP IIb/IIIa inhibitors and were on aspirin after the procedure. Double oral anti-platelet therapy was prescribed for at least 4 weeks after stent implantation.

TIMI flow grade, angiographic myocardial perfusion (myocardial blush grade; MBG), and distal embolization were assessed after primary angioplasty. Analysis of ST-segment resolution was performed by comparison between baseline and 1 to 3 hour 12-lead electrocardiograms. ST-segment resolution was defined as complete (>70%), partial (30%-70%) and no resolution (<30%).

Clinical outcome. Clinical outcome was assessed between 30 days and 1 year after primary angioplasty by telephone interview or at medical visit.

Statistical analysis. Continuous data were expressed as mean ± standard deviation and categorical data as percentage. The ANOVA was appropriately used for continuous variables. The chi-square test or the Fisher’s exact test was used for categorical variables. The difference in event rates between groups during the follow-up period was assessed by the Kaplan-Meier method using the log-rank test. Logistic regression analysis was used to calculate relative risks adjusted for differences in baseline characteristics. All analyses were performed with SPSS statistical software, version 13.0 (SPSS Inc). All P-values are two-tailed and statistical significance was defined as P<.05.

Results

Poor preprocedural TIMI flow (TIMI 0-1) was observed in 1039 patients (63.5%). Patient characteristics are reported in Table 1. Poor preprocedural TIMI flow was associated with higher Killip class at presentation (P=.006), longer time-to-treatment (P=.03), and less often with early administration of GP IIb/IIIa inhibitors (P<.001). As shown in Figure 1, preprocedural TIMI 3 flow was significantly associated with improved postprocedural TIMI 3 flow (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.27-2.1; P<.001), MBG 2-3 (OR, 1.54; CI, 1.29-1.83; P<.001), complete ST-segment resolution (OR, 1.42; CI, 1.23-1.64; P<.001), and less distal embolization (OR, 0.76; CI, 0.58-0.99; P=.041). The relationship was confirmed after adjustment for baseline confounding factors (Killip class, time-to-treatment, early GP IIb/IIIa inhibitors) for postprocedural TIMI 3 flow (adjusted OR, 1.46; CI, 1.12-1.91; P=.005), MBG 2-3 (adjusted OR, 1.46; CI, 1.21-1.76; P<.001), complete ST-segment resolution (adjusted OR,  1.34; CI, 1.14-1.58; P<.001), whereas the association with reduction in the occurrence in distal embolization was less pronounced (adjusted OR, 0.78; CI, 0.59-1.03; P=.081).

By a mean follow-up of 206 ± 158 days, a total of 70 patients (4.3%) had died. Poor pre-procedural recanalization was associated with a significantly higher mortality (Figure 3), confirmed after adjustment for baseline confounding factors (adjusted OR, 0.58; CI, 0.34-0.96; P=.034). No statistically significant difference was observed in survival between abciximab, eptifibatide and tirofiban (P=.2).

Discussion

The main finding of the present study is that among STEMI patients undergoing primary angioplasty with GP IIb/IIIa inhibitors, poor preprocedural TIMI flow was associated with higher incidence of distal embolization and impaired epicardial and myocardial perfusion, larger infarct size, and lower percentage of aborted myocardial infarction. These effects translate into a significant impact on mortality.

Preprocedural TIMI flow, myocardial perfusion, and mortality after primary angioplasty for STEMI. The feasibility and superiority of long-distance transportation for primary angioplasty in comparison with on-site thrombolysis have been confirmed in several trials.⁹ However, the potential time delay for transportation remains a major drawback to primary angioplasty. Time to treatment has recently been shown to be a predictor of mortality not only for thrombolysis but also for primary angioplasty.^4-6 Stone et al¹⁰ found preprocedural but not postprocedural TIMI 3 flow to be an independent predictor of mortality. The role of preprocedural TIMI flow on outcome has been confirmed by Brodie et al,¹¹ who found, in a cohort of 1490 patients treated by primary angioplasty, preprocedural TIMI 2-3 to be associated with the amount of cardiac enzyme release, ejection fraction, and mortality.

In our study, we analyzed the impact of preprocedural TIMI flow on myocardial perfusion, distal embolization, infarct size, abortion of myocardial infarction, and survival. Consistent with previous studies, we found that preprocedural TIMI flow significantly affected myocardial perfusion as evaluated by myocardial blush grade and ST-segment resolution, infarct size, the rate of abortion of myocardial infarction, and mortality. A major explanation for the impact of preprocedural TIMI flow on myocardial perfusion and the extent of myocardial salvage in patients with STEMI treated by primary angioplasty is that the duration of coronary occlusion is a main determinant of myocardial infarct size.¹² Thus, a late reperfusion is expected to result in less myocardial salvage and, conceivably, in a higher mortality, in comparison with an early reperfusion, even when optimal mechanical reperfusion is applied. In our study, the impact of preprocedural TIMI flow on perfusion, infarct size, and mortality was confirmed also in the analysis restricted to patients with postprocedural TIMI 3 flow.

Several factors may explain the preprocedural TIMI-flow dependent mechanism of impaired myocardial perfusion despite optimal epicardial flow. Experimental studies have shown that long ischemic time may induce morphological alterations (swelling of endothelial and cardiac cells, with occlusion or compression of microcirculation) in the cardiac capillaries and arterioles.¹³ Furthermore, recent studies have focused on the role of micro-embolization of atherosclerotic debris, blood clots, and platelet plugs in the microcirculation.¹⁴ A delay in reperfusion may be associated with an older, organized, intracoronary thrombus, in comparison with an early reperfusion. This may result in a higher incidence of distal micro-embolization and poor myocardial perfusion, despite optimal epicardial flow. The importance of early reperfusion is clearly supported by the larger extension of myocardial necrosis observed with poor preprocedural TIMI flow. Previous trials have failed to show benefits from early recanalization obtained by full-dose lysis or combo-therapy at short-term follow-up. However, recent subanalyses from the FINESSE trial¹⁵ showed significant benefits in survival from combo-therapy on 1-year survival in high-risk patients when presenting within the first 4 hours from symptom onset. Significant benefits in primary outcome were also observed in such patients from early abciximab administration. Several additional reports have investigated the benefits from early GP IIb/IIIa inhibitors in primary angioplasty. We have previously shown significant benefits in mortality from early abciximab administration.⁸ Similar findings have been observed in the EUROTRANSFER Registry¹⁶ and in the REAL registry.¹⁷ All these data support the potential role of pharmacological facilitation, which may be considered especially within the first hours from symptom onset (the so called “golden hours,” when early recanalization may with high probability affect the extension of myocardial salvage), and in high-risk patients.

Study limitations. A major limitation of the current study is that patients have been part of a randomized trial, and thus, are potentially selected patients. Furthermore, ST-segment analysis and BMG or perfusion were not analyzed by a single core lab. Furthermore, postprocedural evaluation of myocardial blush may have contributed to the underestimation of myocardial reperfusion, since effective reperfusion may potentially occur later after acute myocardial infarction, despite mechanical revascularization.^18,19

Conclusion

This study shows that among patients with STEMI undergoing primary angioplasty with GP IIb/IIIa inhibitors, poor preprocedural TIMI flow is associated with higher incidence of distal embolization and impaired epicardial and myocardial perfusion, larger infarct size, lower percentage of aborted myocardial infarction, and significantly higher mortality.

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From ¹the Division of Cardiology, Prato Hospital, Prato, Italy, ²Division of Cardiology, Herzzentrum Ludwigshafen, Ludwigshafen, Germany, ³Division of Cardiology, Hospital “De Weezenlanden,” Zwolle, Netherlands, ⁴TIMI Study Group, Cardiovascular Division, Beth Israel Deaconess, Medical Center, Boston, Massachusetts, USA, ⁵II Department of Cardiology, Institute of Cardiology, Jagiellonian University, Krakow, Poland, ⁶Center for Intensive Internal Medicine, University Medical Center, Ljubljana, Slovenia, ⁷Department of Clinical and Experimental Medicine, University of Eastern Piedmont, Novara, Italy, ⁸Division of Cardiology, Hospital de Santa Maria, Lisboa, Portugal, ⁹Siyami Ersek Thoracic and Cardiovascular Surgery Center, Instabul, Turkey, ¹⁰Interventional Cardiology Section, Beth Israel Deaconess Medical Center, Boston, Massachusetts, ¹¹Department of Cardiology, Medical University of Vienna, Vienna, Austria, ¹²3rd Department of Medicine (Cardiology and Emergency Medicine), Wilhelminenspital, Vienna, Austria (KH), ¹³Division of Cardiology, “Maggiore della Carità” Hospital, Eastern Piedmont University, Novara, Italy.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted January 10, 2012, provisional acceptance given February 14, 2012, final version accepted March 15, 2012.
Address for correspondence: Giuseppe De Luca, MD, PhD, Division of Cardiology, University of Eastern Piedmont, Novara, Italy. Email: giuseppe.deluca@maggioreosp.novara.it.