Effects of the Number and Interval of Balloon Inflations during Primary PCI (Full title below)

Effects of the Number and Interval of Balloon Inflations during Primary PCI on the Extent of Myocardial Injury in Patients with STEMI: Does Postconditioning Exist in Real-World Practice?

____________________________ ABSTRACT: Postconditioning reduces infarct size in animal models and clinical studies. The present retrospective study aimed to evaluate the effects of the number and interval delay of balloon inflations during primary percutaneous coronary intervention (PCI) on enzymatic infarct size, myocardial perfusion and cardiac function in patients with ST-segment elevation myocardial infarction (STEMI) in routine clinical practice. Methods. Of the 433 STEMI patients who underwent primary PCI at Vanderbilt University Medical Center from October 2003 to August 2007, 85 (19.6%) met criteria and were enrolled into two groups: those with ≥ 3 versus with ≤ 2 balloon inflations. Peak CK, ST-segment resolution, myocardial blush grade (MBG) and left ventricular (LV) function were compared between the two groups. Correlations of peak CK, MBG and LV ejection fraction (LVEF) with the number, average duration and the first delay interval of balloon inflations were analyzed. A stepwise multiple regression analysis was used to identify the possible determinants of echocardiographic LVEF. Results. The LV end-systolic volume (LVESV) index in the group with ≥ 3 inflations was significantly lower than that with ≤ 2 inflations (33.1 ± 7.9 ml/m2 versus 37.5 ± 11.2 ml/m2; p = 0.036), while LVEF was significantly higher (50.4 ± 6.3% versus 46.1 ± 8.5%; p = 0.009). Post hoc analysis showed peak CK in patients with 4 inflations was significantly lower than that with ≤ 2 inflations (1,698 ± 1,266 IU/L vs. 2,603 ± 1,532 IU/L; p Methods After the approval of Institutional Review Board of Vanderbilt University Medical Center, we reviewed the computerized medical records containing basic clinical information, electrocardiogram (ECG) and laboratory data, as well as imaging data including coronary angiography and echocardiograms for all the patients undergoing primary PCI for STEMI at Vanderbilt University Hospital from October 2003 to August 2007. Study patients. We prespecified the inclusion and exclusion criteria based on those described in the prospective studies6–8 in an effort to minimize confounding factors for analysis. Inclusion criteria included: 1) ≥ 18 years of age; 2) presentation and ECG findings consistent with STEMI (at least 1 mm ST-segment elevation in two contiguous limb leads or at least 2 mm in two precordial leads); 3) presentation within 12 hours of onset of symptoms; 4) occlusion (thrombolysis in myocardial infarction [TIMI] 0 flow grade) of the infarct-related coronary artery (IRA) at the time of cardiac catheterization, and achieving adequate reperfusion (TIMI 3 flow grade) following PCI. Exclusion criteria included: 1) previous acute myocardial infarction (AMI); 2) cardiogenic shock; 3) cardiac arrest; 4) evidence of TIMI-1 or greater flow of the IRA on initial angiography; 5) evidence of coronary collaterals (Rentrop grade ≥ 1) to the culprit region, 5) pre-infarct angina within 48 hours prior to catheterization; and 6) extraction catheter and/or distal protection devices were used. Among 433 patients with STEMI undergoing primary PCI during the study period, 85 (19.6%) met the inclusion and exclusion criteria. Enrolled patients were initially classified into two groups according to the number of additional balloon inflations following reflow (defined by ≥ TIMI-2 flow of the IRA) being accomplished by either guidewire passage or balloon predilatation. The postconditioning algorithms referred to at least 3 cycles of ischemia reperfusion based on the available experimental and clinical studies.4,6–8,11 Thus, the present study population was divided into patients receiving ≥ 3 balloon inflations and those receiving only 1–2 balloon inflations following reflow. The requirements for multiple balloon inflations were clinically indicated and at the discretion of the operators. The indications were long lesions or multiple lesions in tandem requiring multiple predilatations, placement of ≥ 2 stents, or the need for ≥ 1 postdilatation. All the interventional procedures during the period that the data were collected were performed by six interventional cardiologists at Vanderbilt. All six operators were board certified in interventional cardiology, high-volume operators and experienced in primary PCI for AMI. Study endpoints. The following endpoints were compared between the two groups: 1) Peak CK values; 2) resolution of ST-segment elevation on ECG; 3) myocardial blush grade (MBG); 4) left ventricular end-diastolic volume (LVEDV); 5) left ventricular end-systolic volume (LVESV); and 6) LVEF. Peak CK values were obtained from the computerized medical record of each patient. CK values were routinely measured every 6–8 hours for STEMI patients in our hospital. ECGs obtained on admission (first ECG) and shortly after the primary PCI (second ECG) were used to analyze the resolution of ST-segment elevation. The sum of ST-segment elevations was measured 80 ms after the end of the QRS complex in leads I, aVL and V1–V6 for anterior MIs, and leads II, III, aVF, V5 and V6 for non-anterior MIs. Resolution was defined as complete (≥ 70% decrease in ST-segment elevation), partial (30–70%) or no resolution (≤ 30%). Standard interventional techniques were applied during primary PCI. All patients received 325 mg aspirin and 300–600 mg clopidogrel prior to the procedure. Bivalirudin or unfractionated heparin was used as an anticoagulant during the procedure, with the clotting time adjusted to 200–300 seconds. Glycoprotein (GP) IIb/IIIa inhibitors were administered at the operators’ discretion. The number of balloon inflations, the average duration of balloon inflations and the first delay interval of balloon inflations were obtained from the Intervention Procedure Notes in the Witt database. MBG was graded on the final angiography after primary PCI by two blinded, experienced interventionalists based on the visual assessment of contrast opacification of the myocardial territory subtended by the infarct vessel as previously described.12 MBG was defined as: 0 = no myocardial blush or contrast density; 1 = minimal myocardial blush or contrast density; 2 = moderate myocardial blush or contrast density, but less than that obtained during angiography of a contralateral or ipsilateral non-IRA; and 3 = normal myocardial blush or contrast density compared with that obtained during angiography of a contralateral or ipsilateral non-IRA. Echocardiography following the primary PCI was used to evaluate the cardiac functional recovery during hospitalization. Comprehensive 2-dimensional echocardiography was performed using standard methodology in all study patients. All echocardiograms were analyzed by two blinded, experienced echocardiographers. LV volumes and ejection fractions were calculated using a modified Simpson rule and LV volumes were corrected for body surface area. Statistical analysis. Statistical analysis was performed with SAS version 9.1 (SAS Institute, Cary, North Carolina). Continuous variables were expressed as mean ± standard deviation and compared by the Student’s t-test between two groups or by ANOVA and the multiple comparison t-test between > 2 groups. Categorical variables were expressed as percentage and compared by the chi-square test. Pearson’s correlation coefficient was used to correlate peak CK value, MBG and LVEF with the number of balloon inflations, average duration of balloon inflations and the first delay interval of balloon inflations. A stepwise multiple regression analysis was used to assess the possible determinants of echocardiographic LVEF. For the analysis, adjustments were performed with the following variables: age, gender, risk factors, culprit artery, extent of coronary artery disease, symptom onset-to-balloon time as well as the number of balloon inflations, average duration of balloon inflations and the first delay interval of balloon inflations. A p-value Results Characteristics of study patients. The baseline clinical and angiographic characteristics of study patients are summarized in Table 1. Eighty-five patients were divided into either the ≥ 3 inflations group (n = 53) or the ≤ 2 inflations group (n = 32) based on the number of balloon inflations after reflow (≥ TIMI-2 flow of the IRA). There were no significant differences between the two groups in the baseline characteristics except for the average time of balloon inflations in the ≥ 3 inflations group, which was shorter than in the ≤ 2 inflations group. Of note, the onset-to-balloon time was categorized by ranges (i.e., Discussion Current retrospective study showed that STEMI patients receiving ≥ 3 balloon inflations after reflow in the IRA during primary PCI had improved cardiac function, a stepwise multiple regression analysis revealed that the number of balloon inflations was an independent predictor for the echocardiographic LVEF. In addition, compared to the ≤ 2 inflations group, there was a trend toward lower enzymatic infarct size in the ≥ 3 inflations group and a significant reduction in enzymatic infarct size in the 4 inflations group. These results provide further evidence to support the hypothesis that a moderate number of repetitive balloon inflations during primary PCI may evoke a “postconditioning” stimulus and confer cardioprotective effects by attenuating myocardial ischemia-reperfusion injury, and further suggest that postconditioning may have existed in our daily clinical practice to a certain extent. Our data are consistent with previous clinical studies6–10 that postconditioning was effective in reducing infarct size and improving myocardial function. Cardiac function benefit was not reported in the only retrospective study10 and the postconditioning algorithm including the number of balloon inflations, balloon inflation duration, and the time interval before postconditioning, has not been vigorously evaluated in previous studies.11 Therefore, the present study focused on the impact of the number and first delay interval of balloon inflations during primary PCI on cardiac function, myocardial perfusion and enzymatic infarct size in patients undergoing primary PCI for STEMI. The enzymatic infarct size in our study was represented by peak CK values as reported in the studies by Darling10 and Laskey9 rather than the area under the curve (AUC) used in other prospective studies.6-8 This was done because the time points of blood sample collection were not consistent amongst the patient population. According to our group allocation, the peak CK values were initially compared between patients treated with ≥ 3 balloon inflations and those with ≤ 2 inflations after reflow. Our analysis demonstrated a trend toward lower peak CK values in the ≥ 3 balloon inflations group (p = 0.076). Interestingly, post hoc analysis revealed a significant reduction of peak CK values in the 4 inflations group compared to the ≤ 2 inflations group (p Conclusions and Implications The present study demonstrated that a moderate number of repetitive balloon inflations beginning within 10 minutes of reflow during primary PCI may confer cardioprotection from reperfusion injury. These results reinforce the hypothesis that postconditioning may exist in daily clinical practice and contribute to myocardial protection by attenuating reperfusion injury. However, the optimal postconditioning algorithm, including the number of cycles and best time window, needs to be prospectively investigated in a larger cohort. ________________________ From the aDivision of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, bDepartment of Cardiology, Peking University Third Hospital, Beijing, China, cDepartment of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, dSchool of Mathematical Sciences, Graduate University of Chinese Academy of Sciences, Beijing, China. The authors disclose no conflicts of interest regarding the content herein. Manuscript submitted January 26, 2009, provisional acceptance given March 10, 2009, and final version accepted May 4, 2009. Address for correspondence: David X. Zhao, MD, Director, Cardiac Catheterization Laboratory & Interventional Cardiology, Associate Professor of Medicine, Division of Cardiovascular Medicine, 5th floor, Medical Center East, Vanderbilt Heart and Vascular Institute,Vanderbilt University Medical Center, Nashville, TN 37232. E-mail: David.Zhao@Vanderbilt.edu

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