5-Year Prognostic Value of No-Reflow Phenomenon After Percutaneous Coronary Intervention in Patients With Acute Myocardial Infarction

Patients

Between January 2002 and December 2007, 1,861 patients with STEMI presenting within the first 24 h from the symptom onset were admitted to the Deutsches Herzzentrum and 1. Medizinische Klinik Rechts der Isar in Munich, Germany. Patients undergoing conservative therapy (n = 112), thrombolysis (n = 35), or coronary artery bypass surgery as primary reperfusion strategy (n = 18), and patients with missing scintigraphic examination (n = 173), mechanical failures to open the occluded coronary arteries (n = 31), and angiograms of inadequate quality (n = 86) were excluded. Thus, the current study included 1,406 patients with STEMI who underwent primary PCI and had scintigraphic infarct size measurement obtained 7 to 14 days after intervention. The diagnosis of STEMI was established in the presence of chest pain lasting >20 min associated with electrocardiographic changes (ST-segment elevation ≥1 mm in at least 2 extremity electrocardiographic leads or ≥2 mm in at least 2 contiguous precordial leads or left bundle branch block of new onset). The diagnosis was confirmed by coronary angiography in all patients. Glomerular filtration rate was calculated using the Cockroft-Gault formula. Severity of heart failure was assessed according to Killip classification (15). The study was approved by the institutional ethics committee.

Angiographic analysis and definition of no-reflow

Coronary angiography was performed according to standard criteria. Offline analysis of digital angiograms was performed in the core laboratory using an automated edge detection system (CMS, Medis Medical Imaging Systems, Neuen, the Netherlands) by personnel blinded to the clinical diagnosis. Primary PCI (mostly with stent implantation) and periprocedural care were performed according to the standard criteria. Bare-metal stents were mostly used. Antiplatelet therapy consisted of clopidogrel (600 mg as a loading dose followed by 75 mg/day for at least 4 weeks to 6 months) and aspirin (200 mg/day continued indefinitely). Epicardial blood flow in the infarct-related artery and myocardial perfusion grade were graded according to the TIMI (Thrombolysis In Myocardial Infarction) group definitions (16).

The diagnosis of no-reflow required the following criteria: 1) angiographic evidence of reopening of occluded coronary artery and successful stent placement with no evidence of flow-limiting residual stenosis (<50%), dissection, spasm, or apparent thrombus; 2) angiographic documentation of a TIMI flow grade ≤2, or a TIMI flow grade 3 with a TIMI myocardial perfusion grade (TMPG) 0 or 1, at least 10 min after the end of PCI procedure. A TMPG 0 was defined when contrast failed to enter the vasculature; TMPG 1, when contrast slowly entered but failed to exit the vasculature (16).

Scintigraphic study

The ^99mTc-sestamibi single-photon emission computed tomography (SPECT) was performed 7 to 14 days after PCI. Patients received an intravenous injection of 27 mCi (1,000 MBq) of ^99mTc-sestamibi, and SPECT was performed 6 to 8 h after injection of radioactive agent. A multihead camera system, equipped with low energy and high resolution collimators, was used for myocardial imaging. Images were acquired in a 64 × 64 matrix by an acquisition time of 40 s per image. With dedicated software (ICON version 6.0.2, Siemens Medical Systems, Inc., Hoffman Estates, Illinois), transaxial slices were reconstructed. A volumetric sampling tool was applied to create polar maps of relative distribution throughout the entire left ventricle. Each polar map was normalized to its individual maximum. The defect size was defined as the <50% uptake area. All measurements were performed in the scintigraphic core laboratory by investigators unaware of clinical or angiographic data.

End points and follow-up

The primary outcome of this analysis was 5-year mortality. The follow-up information was obtained by a telephone call at 30 days, a visit at 6 months, a telephone call at 1 year, and annual telephone calls thereafter. Patients who had cardiac complaints underwent a complete clinical, electrocardiographic, and laboratory evaluation. Information about death was obtained from hospital records, death certificates, or telephone contact with relatives of the patient or referring physician. The follow-up information was obtained by personnel blinded to the clinical characteristics of the patients.

Statistical analysis

Data are presented as median (with 25th and 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 Wilcoxon rank-sum test. Five-year mortality was estimated by applying the Kaplan-Meier method and log-rank test, which allowed the calculation of odds ratios [ORs] (with 95% confidence intervals [CIs] and respective p values) associated with no-reflow or reflow after primary PCI. Univariable and multivariable Cox proportional hazards models were used to assess the association between no-reflow and mortality. All variables of Tables 1 and 2⇓⇓plus no-reflow and infarct size were entered into the univariable model with 5-year mortality as the dependent variable; variables that resulted significant (p < 0.05) from univariable Cox proportional hazards model were entered into the multivariable Cox proportional hazards model using the backward variable selection method. We compared the discriminatory power of multivariable models regarding 5-year mortality with and without the variable no-reflow by calculating the integrated discrimination improvement, according to Pencina et al. (17).

All analyses were performed using the S-PLUS statistical package (Insightful Corp., Seattle, Washington). A p < 0.05 was considered to indicate statistical significance.

Baseline characteristics

Baseline characteristics of the patients are shown in Table 1. Patients with no-reflow were of older age, had a higher proportion of patients with prior coronary artery bypass surgery, and higher values of peak troponin, peak creatine kinase-myocardial band, and C-reactive protein; and lower values of glomerular filtration rate compared with patients with reflow. Furthermore, patients with no-reflow were less often smokers and had a longer time interval from symptom onset to hospital admission than patients with reflow. Patients with no-reflow had a tendency for being less often in Killip class I than were patients with reflow. Angiographic data are shown in Table 2. Multivessel disease was more often encountered among patients with no-reflow than among patients with reflow. The group with no-reflow had lower left ventricular ejection fraction and higher proportion of patients with baseline TIMI flow grades 0 and 1 compared with patients with reflow (Table 2). Bare-metal stents were used in 274 patients with no-reflow and in 630 patients with reflow (66.8% vs. 66.3%; p = 0.20).

No-reflow and scintigraphic infarct size

In the whole study patients, infarct size median (25th to 75th percentiles) in the 7 to 14 days SPECT imaging was 10.0% (2.0% to 24.0%) of the left ventricle. The tertiles of infarct size were as follows: first tertile, 0% to 5.0% of the left ventricle; second tertile, >5.0% to 18.1% of the left ventricle; third tertile >18.1% of the left ventricle. Infarct size in the 7 to 14 days SPECT imaging was 15.0% (6.0% to 29.0%) of the left ventricle in patients with no-reflow versus 8.0% (2.0% to 21.0%) of the left ventricle in patients with reflow (p < 0.001) (Fig. 1).

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Figure 1

Infarct Size in the 7 to 14 Days Scintigraphy in Groups With Reflow and No-Reflow

Data are medians with 25th to 75th and 5th to 95th percentiles. LV = left ventricle.

No-reflow and 5-year mortality

There were 132 deaths during the follow-up: 59 deaths occurred among patients with no-reflow and 73 deaths occurred among patients with reflow (Kaplan-Meier estimates of 5-year mortality 18.2% and 9.5%, respectively; OR: 2.02, 95% CI: 1.44 to 2.82; p < 0.001) (Fig. 2).

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Figure 2

Kaplan-Meier Curves of 5-Year Mortality

Red line= reflow group; blue line= no-reflow group. CI = confidence interval; HR = hazard ratio.

Deaths were of cardiovascular origin in 90 patients (68.2%). Of them, 42 deaths occurred in patients with no-reflow and 48 deaths occurred in patients with reflow (estimates of 5-year mortality 12.4% and 6.3%, respectively; OR: 2.18, 95% CI: 1.46 to 3.27; p < 0.001).

No-reflow, infarct size, and 5-year mortality

Five-year mortality associated with no-reflow was analyzed according to tertiles of infarct size in the 7 to 14 days SPECT imaging. The data show that with the increase in infarct size, the frequency of no-reflow phenomenon increased significantly (p for trend <0.001). In each of the infarct size tertiles, the presence of no-reflow was associated with an increased risk of 5-year mortality (Table 3).

The univariable correlates (p < 0.05) of 5-year mortality were no-reflow, age, sex, body mass index, diabetes mellitus, arterial hypertension, previous myocardial infarction, previous coronary artery bypass surgery, anterior infarct location, Killip class, glomerular filtration rate, C-reactive protein, left ventricular ejection fraction, multivessel disease, infarct-related artery, and scintigraphic infarct size. After application of backward variable selection method in the multivariable Cox model, 7 variables (no-reflow, age, diabetes, Killip class, baseline C-reactive protein, multivessel disease, and infarct size) remained as independent correlates of 5-year mortality (Table 4).The inclusion of the no-reflow in the multivariable model was associated with an improved discriminatory power of the model regarding the prediction of the 5-year mortality (absolute integrated discrimination improvement = 0.0108, relative integrated discrimination improvement = 7.0%; p = 0.028).

Study limitations

The present study focused primarily on the long-term mortality of patients with no-reflow after primary PCI. We accept as a limitation that we could not provide information on the time-course of no-reflow phenomenon and the evolution of TIMI flow grade after intervention. Although pharmacological agents were occasionally used to treat no-reflow phenomenon after primary PCI, these agents were not systematically used, and thus their therapeutic effects can not be tested in the setting of present study. Data on angiographic thrombotic burden in the infarct-related artery were not available. However, missing thrombotic burden data do not weaken our main analysis of the association between no-reflow and long-term mortality.