CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY
Prognostic Significance of Epicardial Blood Flow Before and After Percutaneous Coronary Intervention in Patients With Acute Coronary Syndromes
Gjin Ndrepepa, MD*,*,
Julinda Mehilli, MD*,
Stefanie Schulz, MD*,
Raisuke Iijima, MD*,
Dritan Keta, MD*,
Robert A. Byrne, MD*,
Jürgen Pache, MD*,
Melchior Seyfarth, MD*,
Albert Schömig, MD*, and
Adnan Kastrati, MD*
* Deutsches Herzzentrum, Munich, Germany
1. Medizinische Klinik rechts der Isar, Technische Universität, Munich, Germany.
Manuscript received March 10, 2008;
revised manuscript received April 28, 2008,
accepted May 5, 2008.
* Reprint requests and correspondence: Dr. Gjin Ndrepepa, Deutsches Herzzentrum, Lazarettstrasse 36, 80636 München, Germany. (Email: ndrepepa{at}dhm.mhn.de).
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Abstract
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Objectives: The aim of the study was to assess the relationship between baseline and post-procedural Thrombolysis In Myocardial Infarction (TIMI) epicardial blood flow grade and mortality in patients with acute coronary syndromes (ACS) who were treated with early percutaneous coronary intervention (PCI).
Background: The impact of baseline and post-procedural TIMI flow grade on mortality in patients with ACS has been insufficiently studied.
Methods: This prospective registry included 10,455 patients with ACS who underwent coronary angiography and PCI: 2,853 patients with ST-segment elevation acute myocardial infarction, 3,060 patients with non–ST-segment elevation acute myocardial infarction, and 4,542 patients with unstable angina. The primary outcome was 1-year mortality.
Results: At 1 year, there were 976 deaths: 117 deaths among patients with TIMI flow grade 0 to 1, 105 deaths among patients with TIMI flow grade 2, and 754 deaths among patients with TIMI flow grade 3 (Kaplan-Meier estimates of mortality 28.3%, 18.4%, and 8.0%, respectively; odds ratio: 1.66, 95% confidence interval [CI]: 1.57 to 1.76, p < 0.001, for TIMI flow grade 0 to 1 vs. TIMI flow grade 2 and odds ratio: 2.51, 95% CI: 2.06 to 3.06, p < 0.001, for TIMI flow grade 2 vs. TIMI flow grade 3). By using the Cox proportional hazards survival model, we identified post-PCI TIMI flow grade (hazard ratio: 0.60, 95% CI: 0.52 to 0.70; p < 0.001, for 1 grade increase in TIMI flow grade) but not baseline TIMI grade (hazard ratio: 1.08, 95% CI: 0.96 to 1.22; p = 0.20, for 1 grade increase in TIMI flow grade) as an independent correlate of 1-year mortality.
Conclusions: In patients with ACS treated with early PCI, post-procedural TIMI flow grade but not baseline TIMI flow grade is an independent correlate of 1-year mortality.
Key Words: acute coronary syndrome • mortality • percutaneous coronary intervention • TIMI flow grade
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Abbreviations and Acronyms
| | ACS = acute coronary syndromes | | CI = confidence interval | | HR = hazard ratio | | OR = odds ratio | | PCI = percutaneous coronary intervention | | TIMI = Thrombolysis In Myocardial Infarction |
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The completeness of restoration of the epicardial blood flow after recanalization of infarct-related artery has been quantified with the Thrombolysis In Myocardial Infarction (TIMI) grading system (1). The beneficial effects of full restoration of the epicardial coronary flow (TIMI flow grade 3) and the detrimental effects of failure to restore epicardial coronary flow (TIMI 0 to 1) are well known (2). However, controversy still exists with regard to outcomes in patients with partial restoration of the epicardial coronary flow (TIMI flow grade 2) after reperfusion therapy (3–7). In the past, restoration of TIMI flow grade 2 was considered as procedural success (3,4), and the results were reported with TIMI flow grades 2 and 3 grouped together. Later, after it was demonstrated that results in patients with TIMI flow grade 2 did not differ from those in patients with TIMI flow grade 0 to 1 (5–7) or were even worse (8), TIMI flow grade 2 was considered as suboptimal reperfusion and grouped together with TIMI flow grade 0 to 1 as TIMI flow grade  2 (9–12). We undertook this study to assess the relationship between baseline and post-procedural TIMI flow grade and 1-year mortality in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI).
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Methods
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Patients.
This prospective registry included 10,455 consecutive patients with ACS who underwent diagnostic coronary angiography and PCI in the Deutsches Herzzentrum and 1. Medizinische Klinik rechts der Isar between September 1997 and December 2006: 2,853 patients with ST-segment elevation acute myocardial infarction, 3,060 patients with non–ST-segment elevation acute myocardial infarction, and 4,542 patients with unstable angina.
Angiographic evaluation and stent implantation.
Coronary angiography was performed according to standard criteria. Angiographic data were analyzed with the same Quantitative Angiographic Core Laboratory. Coronary artery disease was confirmed by the presence of coronary stenoses  50% lumen obstruction in at least 1 of the 3 main coronary arteries. A culprit lesion was described in the presence of an acute occlusion, intraluminal filling defects (or thrombus), ulcerated plaques with a contrast-filled pocket protruding into plaque with or without delayed contrast wash-out, extraluminal contrast, dissection, or intraluminal flaps (13). Offline analysis of digital angiograms was performed in the core laboratory with an automated edge detection system (CMS, Medis Medical Imaging Systems, Neuen, the Netherlands). The initial and post-procedural blood flow in the artery owning the culprit lesion was quantified with the TIMI grading system (1). Stent implantation and periprocedural care were performed according to standard criteria. Bare-metal stents were mostly used. Post-interventional antiplatelet therapy consisted of ticlopidine (500 mg/day) or clopidogrel (300 or 600 mg as a loading dose followed by 75 mg/day for at least 4 weeks to 6 months) and aspirin (200 mg/day administered orally and continued indefinitely).
End point and follow-up.
The primary outcome of this analysis was 1-year mortality. The occurrence of myocardial infarction also was assessed. The follow-up protocol after discharge consisted of a phone interview at 1 month after the procedure, a visit at 6 months, and a phone interview at 12 months. Information about death was obtained from hospital records, death certificates, or phone contact with relatives of the patient or attending physician. The diagnosis of myocardial infarction was made according to the TIMI criteria (1).
Patients were advised to present to the outpatient clinic or their referring physicians if they developed chest pain or other cardiac symptoms. In case of symptoms, at least 1 clinical, laboratory, or electrocardiographic check-up was performed.
Statistical analysis.
Data are presented as median (25th; 75th percentiles) or counts and proportions (percentages). The distribution of the data was analyzed with the 1-sample Kolmogorov-Smirnov test. Categorical data were compared with the chi-square test. Continuous data were compared with the Kruskal-Wallis test. Survival analysis was performed by applying the Kaplan-Meier method. Differences in survival were assessed with the log-rank test. The Cox proportional hazards survival model was used to assess the association of the TIMI flow grade with 30-day and 1-year mortality while adjusting for potential confounders. Variables entered into the model were age, gender, diabetes, arterial hypertension, smoking, hypercholesterolemia, previous myocardial infarction, previous coronary artery bypass surgery, clinical presentation, cardiogenic shock, serum creatinine, left ventricular ejection fraction, extent of coronary artery disease, type of vessel, culprit lesion location, vessel size, glycoprotein IIb/IIIa inhibitors, baseline TIMI flow grade, and post-PCI TIMI flow grade. Analyses were performed with the S-plus statistical package (S-PLUS, Insightful Corp., Seattle, Washington). A p value <0.05 was considered to indicate statistical significance.
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Results
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A total of 10,455 patients with ACS underwent coronary angiography and were treated with PCI. In 9,217 patients (88.2%), coronary stents were implanted; the remaining 1,238 patients (11.8%) were treated with balloon angioplasty. Because there were no significant differences in 1-year mortality among patients with post-PCI TIMI flow grade 0 or 1 (26% vs. 34%), these patients were grouped together as TIMI flow grade 0 to 1. Baseline characteristics according to post-procedural TIMI flow grade are shown in Table 1. Patients with a post-PCI TIMI flow grade 0 to 1 were older and were more likely to be diabetic, to have had previous myocardial infarction or previous coronary artery bypass surgery, and they presented more often with cardiogenic shock and had greater levels of troponin than patients with a TIMI flow grade 2 or 3. Hypercholesterolemia was observed slightly less often in patients with a TIMI flow grade 0 to 1 compared with 2 other TIMI flow grade groups. Other baseline characteristics that differed significantly among patients with various TIMI flow grades were arterial hypertension, clinical presentation, creatine kinase-myocardial band activity, and creatinine level.
Angiographic data are shown in Table 2. Patients with a TIMI flow grade 0 to 1 had more reduced left ventricular systolic function and had a greater proportion of patients with multivessel disease and a baseline TIMI flow grade 0 to 1 than patients with TIMI flow grades 2 or 3. Figure 1
shows the relationship between baseline and post-PCI TIMI flow grades.
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Figure 1 Baseline and Post-PCI TIMI Grades
Relationship between baseline TIMI flow grade and TIMI flow grade immediately after PCI. PCI = percutaneous coronary intervention; TIMI = Thrombolysis In Myocardial Infarction.
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Outcome according to baseline TIMI flow grade.
There were 3,511 patients with baseline TIMI flow grade 0 to 1, 1,864 patients with baseline TIMI flow grade 2, and 5,080 patients with TIMI flow grade 3. At 30 days, there were 302 deaths among patients with TIMI flow grade 0 to 1, 102 deaths among patients with TIMI flow grade 2, and 154 deaths among patients with TIMI flow grade 3 (Kaplan-Meier estimates of mortality, 8.6%, 5.5%, and 3.0%, respectively; odds ratio [OR]: 1.60, 95% confidence interval [CI]: 1.48 to 1.74, p < 0.001 for TIMI flow grade 0 to 1 vs. TIMI flow grade 2 and OR: 1.85, 95% CI: 1.43 to 2.39, p < 0.001 for TIMI flow grade 2 vs. TIMI flow grade 3). There were no significant differences in the occurrence of myocardial infarction within the first 30 days after PCI according to baseline TIMI flow grade (2.2% [n = 77] in TIMI flow grade 0 to 1, 2.4% [n = 45] in TIMI flow grade 2, and 2.1% [n = 105] in TIMI flow grade 3).
At 1 year, there were 425 deaths among patients with TIMI flow grade 0 to 1, 187 deaths among patients with TIMI flow grade 2, and 364 deaths among patients with TIMI flow grade 3 (Kaplan-Meier estimates of mortality, 12.1%, 10.0%, and 7.2%, respectively; OR: 1.23, 95% CI: 1.17 to 1.30, p < 0.001 for TIMI flow grade 0 to 1 vs. TIMI flow grade 2 and OR: 1.44, 95% CI: 1.19 to 1.73, p < 0.001 for TIMI flow grade 2 vs. TIMI flow grade 3. Again, there were no significant differences in the occurrence of myocardial infarction within the first year after PCI according to baseline TIMI flow grade (3.3% [n = 116] in TIMI flow grade 0 to 1, 3.4% [n = 64] in TIMI flow grade 2 and 3.1% [n = 160] in TIMI flow grade 3).
There were 3,209 patients with TIMI flow grade 0 to 1, 1,762 patients with TIMI flow grade 2, and 4,926 patients with TIMI flow grade 3 who survived the first month after PCI. Between 1 and 12 months after PCI, there were 123 deaths among patients with TIMI flow grade 0 to 1, 85 deaths patients among patients with TIMI flow grade 2, and 210 deaths among patients with TIMI flow grade 3 (Kaplan-Meier estimates 3.2%, 4.8%, and 4.3%, respectively; OR: 0.79, 95% CI: 0.60 to 1.04, p = 0.25 for TIMI flow grade 0 to 1 vs. TIMI flow grade 2 and OR: 1.14, 95% CI: 0.88 to 1.47, p = 0.32, for TIMI flow grade 2 vs. TIMI flow grade 3).
30-day outcome according to post-PCI TIMI flow grade.
The 30-day outcome of patients according to the TIMI flow grades is shown in Table 3
(first part). The proportions of patients who died or had reinfarction were decreased with the increase in the post-PCI TIMI flow grade from grade 0 to 1 to grade 3. Table 4
shows ORs with 95% CI regarding 30-day outcome in groups with a TIMI flow grade 0 to 1 vs. TIMI flow grade 2 and TIMI flow grade 2 versus TIMI flow grade 3.
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Table 4 Odds Ratio (95% CI) for TIMI Flow Grade 0 to 1 Versus TIMI Flow Grade 2 and TIMI Flow Grade 2 Versus TIMI Flow Grade 3
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1-year outcome according to post-PCI TIMI flow grade.
The 1-year outcome is shown in Table 3. At 1 year, there were 117 deaths among patients with TIMI flow grade 0 to 1, 105 deaths among patients with TIMI flow grade 2, and 754 deaths among patients with TIMI flow grade 3 (Kaplan-Meier estimates of mortality 28.3%, 18.4%, and 8.0%, respectively; OR: 1.66, 95% CI: 1.57 to 1.76, p < 0.001 for TIMI flow grade 0 to 1 vs. TIMI flow grade 2 and OR: 2.51, 95% CI: 2.06 to 3.06, p < 0.001 for TIMI flow grade 2 vs. TIMI flow grade 3) (Table 4, Fig. 2). Table 4 shows ORs (95% CIs) regarding 1-year outcome in groups with a TIMI flow grade 0 to 1 versus TIMI flow grade 2 and TIMI flow grade 2 versus TIMI flow grade 3.
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Figure 2 1-Year Mortality According to Post-PCI TIMI Flow Grade
Kaplan-Meier curves of 1-year mortality in patients according to post-PCI TIMI flow grades. CI = confidence interval; OR = odds ratio; other abbreviations as in Figure 1.
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Results of multivariable analysis.
The Cox proportional hazards survival model was used to test the association of TIMI flow grade with 30-day and 1-year mortality (see Methods section for variables entered into the model). The model showed that post-PCI TIMI flow grade was an independent correlate of 30-day mortality (hazard ratio [HR]: 0.59, 95% CI: 0.49 to 0.71; p < 0.001, for 1 grade increase in TIMI flow grade) and of 1-year mortality (HR: 0.60, 95% CI: 0.52 to 0.70; p < 0.001, for 1 grade increase in TIMI flow grade). Baseline TIMI flow grade was not an independent correlate of either 30-day mortality (HR: 0.88, 95% CI: 0.74 to 1.05; p = 0.15, for 1 grade increase in TIMI flow grade) or 1-year mortality (HR: 1.08, 95% CI: 0.96 to 1.22; p = 0.20, for 1 grade increase in TIMI flow grade). There was no significant interaction between baseline TIMI flow grade and ACS form in predicting 1-year mortality (p = 0.26).
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Discussion
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In this study, we investigated the relationship between TIMI flow grade achieved after PCI (mostly coronary stenting) and mortality in a large prospective registry, including more than 10,000 patients with ACS. A unique characteristic of this registry is that all patients were treated with PCI. The main findings of this study are as follows: 1) Post-PCI TIMI flow grade was strongly associated with 30-day and 1-year mortality in patients with ACS. The association between post-PCI TIMI flow and mortality is independent of cardiovascular risk factors or clinical characteristics, including baseline TIMI grade and ACS presentation. 2) Patients with TIMI flow grade 2 have mortality rates intermediate to those of patients with TIMI flow grade 0 to 1 and TIMI flow grade 3. 3) Although baseline TIMI flow grade predicts 30-day and 1-year mortality (in univariate analysis), an adjustment in the multivariable model for other characteristics, including post-PCI TIMI flow grade, attenuated the strength of association to the level of statistical insignificance. A separate analysis of deaths within the first 30 days and from 1 month to 1 year showed that baseline TIMI flow grade affected early (30-day) mortality, but it did not influence subsequent mortality from 1 month to 1 year after PCI.
Findings regarding the impact of the baseline and post-procedural TIMI flow grade on mortality deserve attention. We observed an association between baseline TIMI flow grade and 30-day and 1-year mortality. Furthermore, separate analyses of deaths occurring within the first 30 days and 1-month to 1-year time intervals showed that baseline TIMI flow grade affected 30-day mortality but it did not affect deaths occurring 1 month to 1 year after PCI. After adjustment in the multivariable analysis for other potential confounders, including post-PCI, the baseline TIMI flow grade was not an independent correlate of either 30-day or 1-year mortality. This finding is at variance with some previous studies of patients with acute myocardial infarction undergoing PCI in which baseline TIMI flow grade predicted early and late survival (11,14). It has to be stressed that, in both these studies, the baseline TIMI flow grade-mortality association was at the edge of statistical significance and that TIMI flow grades 2 were grouped together and compared with TIMI flow grade 3 (11,14). Instead, in our study, the association between baseline TIMI flow grade and mortality was assessed for 1 grade difference in TIMI flow.
Theoretically, differences in patient populations between our study (patients with ACS) and these studies (patients with acute myocardial infarction) could be another source of discrepancy. Scintigraphic studies have shown that preserved blood flow in the infarct-related in patients with acute myocardial infarction is associated with a smaller area at risk, a smaller infarct, and better recovery of left ventricular function (15). However, we did not find any significant interaction between baseline TIMI flow grade and ACS form in predicting mortality. Finally, there is a possibility that the association between baseline TIMI flow grade and outcome may be overridden by a high rate of TIMI flow grade 3 achieved with PCI.
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Conclusions
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Data from this large prospective registry of patients with ACS undergoing PCI showed that post-procedural TIMI flow grade but not baseline TIMI flow grade was an independent predictor of 1-year mortality. Patients with a post-PCI TIMI flow grade 2 showed a mortality that was intermediate between that of patients with TIMI flow grades 0 to 1 and 3.
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References
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Abstract
Methods