Author + information
- Received January 20, 2009
- Revision received April 20, 2009
- Accepted April 20, 2009
- Published online September 15, 2009.
- Murat Sezer, MD⁎,⁎ (, )
- Arif Çimen, MD⁎,
- Emre Aslanger, MD⁎,
- Ali Elitok, MD⁎,
- Berrin Umman, MD⁎,
- Zehra Buğra, MD⁎,
- Ebru Yormaz, MD†,
- Cüneyt Türkmen, MD†,
- I.şık Adalet, MD†,
- Yilmaz Nişanci, MD⁎ and
- Sabahattin Umman, MD⁎,†
- ↵⁎Reprint requests and correspondence:
Dr. Murat Sezer, Istanbul Faculty of Medicine, Department of Cardiology, Istanbul University, Capa-Istanbul, Turkey
Objectives The purpose of this study was to investigate the reflections of the improvement in microvascular perfusion provided by adjuvant intracoronary streptokinase (ICSK) on late-phase infarct size and left ventricular volumes and functions.
Background It has been shown that ICSK given immediately after primary percutaneous coronary intervention (PCI) improves myocardial perfusion in the early days of ST-segment elevation acute myocardial infarction.
Methods Ninety-five patients undergoing primary PCI were randomized to ICSK 250 kU (n = 51) or no additional therapy (n = 44). Two days later, coronary hemodynamic indexes were measured to evaluate tissue-level perfusion. After 6 months, angiography, echocardiography, and technetium-99m single-photon emission computed tomography (SPECT) were performed.
Results At 2 days, all indexes of microvascular function were significantly better in the ICSK group than in the control group, including coronary flow reserve (2.5 vs. 1.7, p < 0.001) and index of microvascular resistance (20.2 vs. 34.2, p < 0.001). At 6 months, infarct size (22.7% vs. 32.9%; p = 0.003) and left ventricular end-systolic (41.1 ml vs. 60.9 ml; p = 0.009) and end-diastolic volumes (95.5 ml vs. 118.3 ml; p = 0.006) were significantly smaller, and the ejection fraction was significantly higher (57.2% vs. 51.8%; p = 0.018) in the ICSK group compared with the control group.
Conclusions In this study, it has been demonstrated that low-dose ICSK given immediately after primary PCI significantly limits long-term infarct size and preserves left ventricular volumes and functions. (Effect of Complementary Intracoronary Streptokinase Administration Immediately After Primary Percutaneous Coronary Intervention on Microvascular Perfusion and Late Term Infarct Size in Patients With Acute Myocardial Infarction; NCT00302419)
- acute myocardial infarction
- primary percutaneous coronary intervention
- infarct size
- coronary microcirculation
- intracoronary streptokinase
- reperfusion injury
Mechanical revascularization of the infarct-related artery (IRA) is the most effective treatment modality in ST-segment elevation myocardial infarction (STEMI). However, ongoing myocardial damage despite the successful elimination of epicardial occlusion limits its efficacy. If the tissue damage and stasis that develop in infarcted myocardial segments are considered together, de novo fibrin formation at the microvascular level will be found to be unavoidable. There is a bulk of evidence pointing out that autochthonous microvascular fibrin, vessel wall components, circulating blood cells, and fibrinogen supplied by the reperfusion together participate in the increase of microvascular resistance (1,2). Based on this hypothesis, in a recent study by our group, it has been shown that low-dose intracoronary fibrin/fibrinogenolytic agent (streptokinase) administration immediately after primary percutaneous coronary intervention (PCI) significantly improves myocardial perfusion, as was evidenced by several perfusion parameters on the second day (3). Nevertheless, the sample size of the study was not enough to assess the efficacy of the therapy on long-term parameters such as infarct size, left ventricular (LV) volumes, and LV function. In the present study, the sample size was increased to clarify the effect of adjunctive intracoronary streptokinase (ICSK) administration in the setting of primary PCI on long-term infarct size and LV function.
Patients within the first 12 h of STEMI undergoing primary PCI were enrolled. Major exclusion criteria were: history of prior myocardial infarction, Thrombolysis In Myocardial Infarction (TIMI) flow grade 2 or 3 at IRA, culprit lesion in a saphenous vein graft, and left bundle branch block. Written informed consent was obtained from all patients. The study was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by our hospital ethics committee.
Immediately after diagnostic angiography, eligible patients were assigned to either the ICSK or the control group based on a computer-generated random sequence. In both groups, IRA was stented after balloon dilation. All patients received 300 mg of aspirin, a loading dose of 600 mg of clopidogrel, intracoronary unfractionated heparin at a dose of 100 U/kg, and tirofiban as a bolus of 0.1 μg/kg in 3 min, followed by a continuous infusion of 0.15 μg/kg/min for 12 h. Invasive procedures were done with a femoral approach.
In the ICSK group, immediately after recanalizing the IRA, 250 kU of streptokinase diluted with 20 ml of saline was infused through the guiding catheter within 3 min. The control group received no additional treatment. Final angiographic recordings were performed to assess the corrected Thrombolysis In Myocardial Infarction frame count (cTFC) and myocardial blush grade (MBG). Electrocardiograms were recorded immediately and 90 min after the procedure to assess ST-segment resolution.
Microvascular perfusion assessments
All trial subjects were recatheterized for evaluation of microvascular function on the second day after PCI. A pressure-temperature sensor-tipped guide wire (Pressure wire sensor 5, Radi Medical Systems, Uppsala, Sweden) was used for coronary hemodynamic assessment. Papaverine was given as an intracoronary bolus to induce maximal hyperemia. The thermodilution-derived coronary flow reserve and the index of microvascular resistance were calculated as described previously (3). Coronary angiography was also performed to assess cTFC and MBG.
Diastolic deceleration time was measured from the coronary flow velocity spectrum in patients whose IRA was the left anterior descending coronary artery by transthoracic echocardiography on the second day as previously reported (3).
Echocardiography, angiography, and technetium-99m sestamibi single-photon emission computed tomography (SPECT) were performed 6 months after primary PCI. LV end-diastolic and -systolic volumes were measured and their percent changes relative to second day values were calculated. cTFC and MBG were reassessed from the follow-up angiogram. Technetium-99m sestamibi SPECT was used to measure infarct size, which was expressed as a percentage of total myocardium (4) by a nuclear medicine specialist blinded to the study groups. All coronary hemodynamic, angiographic, echocardiographic, electrocardiographic, and scintigraphic data were stored and analyzed off-line by investigators blind to the study groups.
Study end points
The primary end point of this study was the long-term LV infarct size. Secondary end points included LV volumes and function, and major adverse cardiac events such as reinfarction, revascularization, and death.
Sample size was calculated using GraphPad Instat software (La Jolla, California). Calculations were done to estimate the necessary sample size to detect a 30% difference between the ICSK and control groups for infarct size (alpha: 0.05, beta: 0.20, power: 0.80). Estimated mean value and standard deviations for infarct size were obtained from the previous study (3). Necessary sample size was calculated as 39 patients for each group. Then, allocation was continued based on the random sequence generated for the pilot study. In this manner, 54 more eligible patients were randomized consecutively in addition to 41 patients of the pilot study in adherence with the same protocol. Final total patient numbers in the ICSK and control groups attained were 51 and 44, respectively.
All statistical tests were performed with the Statistical Package for the Social Sciences program (SPSS Inc., Chicago, Illinois). Group proportions were compared by the chi-square or Fisher exact tests. Group means were compared by the Student ttest for independent groups. Categorical variables were compared by the chi-square test. All analyses performed were repeated for the anterior infarction subgroup. Group means were adjusted for age, pain-to-balloon time, hypertension, diabetes, pre-infarction angina, no-reflow, side branch embolization, and angiographically-measured area at risk and compared by analysis of covariance (ANCOVA). All of the variables were distributed normally according to the Kolmogorov-Smirnov test except left ventricular end-systolic volumes at 2 days and at 6 months. For these 2 variables, ANCOVA was performed using their logarithmic values. The difference between groups with regard to MBG was first analyzed by the chi-square test, and then a logistic regression model including the above-mentioned covariates was built. Statistical significance was assigned to p values <0.05.
Study patients and angiographic outcomes
Between October 2004 and August 2007, 95 patients were enrolled in the trial and allocated to either the ICSK (n = 51) or control group (n = 44) (Fig. 1).There was no significant difference between the 2 groups with respect to baseline demographic, clinical, and angiographic characteristics, except the mean age was lower and the pain-to-balloon time was longer in the ICSK group (Table 1).
The IRA was successfully opened in all cases. No major bleeding occurred. Five access site complications were encountered (2 minimal bleeding in each group and 1 pseudoaneurysm in the ICSK group). All were managed with manual compression.
Assessment of microcirculation
Microvascular perfusion was significantly better in the ICSK group than in the control group, as assessed in all perfusion parameters at the second day as shown in Table 2.Immediately after primary PCI, there was no significant difference between the 2 groups with regard to cTFC and MBG. However, at 48 h, the cTFC was lower and MBGs 2/3 were more frequent (86% vs. 36%; p < 0.001 adjusted) in the ICSK group (Table 2).
There was no difference between the 2 groups with respect to percent resolution of ST-segment deviation 90 min after primary PCI (Table 2).
Forty-five patients in the ICSK group and 35 in the control group underwent SPECT imaging at 6.2 ± 1.7 months. Infarct size was significantly smaller in the ICSK group than in the control group (22.7% vs. 32.9%, p = 0.003, adjusted) (Table 3,Fig. 2).
Angiographic and echocardiographic follow-ups were obtained in 48 patients in the ICSK and 37 in the control group. Whereas echocardiographic LV ejection fraction was not significantly different between the groups at the second day, it was higher in the ICSK group in the long term (57.2% vs. 51.8%, p = 0.018, adjusted). LV volumes were significantly smaller and MBG and cTFC were significantly better in the ICSK group in the long term as well (Tables 2 and 3, Fig. 2).
Major adverse cardiac events at follow-up
One patient in the ICSK and 2 in the control group underwent surgical revascularization, and 1 patient in the ICSK group had reinfarction at 1 month. Three cardiac deaths in the control group and 2 in the ICSK group occurred during the follow-up period.
Studies aiming to understand and prevent myocardial damage developing after reperfusion are mostly targeted to reperfusion injury and atherothrombotic embolization downstream of the microvasculature.
Reperfusion injury is described as a myocardial hazard caused by oxygen free radicals, altered calcium handling, microvascular endothelial dysfunction, and platelet, neutrophil, and complement activation (5). Despite various therapeutic interventions addressed to overcome reperfusion injury (6,7), no remarkable progress could be achieved by then. Furthermore, demonstrating the beneficial effect of supersaturated oxygen infusion to the infarcted region in patients with anterior infarction made the oxygen toxicity concept quite questionable (8).
Atherothrombotic embolization might be the explanation for ongoing myocardial damage after reperfusion. But discrepant results of the distal protection studies suggested that distal embolization does not look like a determining mechanism alone (9,10).
There are several reports suggesting that another mechanism may play a role in microvascular malperfusion. It has been demonstrated in ischemia/reperfusion models that de novo fibrin depositions occur in the microvasculature of the brain (11), small intestine (12), and kidney (13). This autochthonous fibrin mass binds to endothelial junctional adhesion molecules (VE-cadherin), constitutes a mesh, and tends to persist in the microvasculature (14). On the other hand, although eliminating epicardial occlusion re-establishes perfusion, it also supplies circulating blood cells downstream that later get entrapped in the microvasculature that contains the fibrin mesh. Blood cells create obstructive plugs and cause significant congestion by enmeshing passively or binding to fibrin actively with their receptors (15). In this slow-flow condition, fibrinogen also contributes to impeding flow via facilitating blood cell aggregation and mediating the inflammatory process (16,17).
In light of the above-mentioned facts, reperfusion injury might be considered as the consequence of insufficient perfusion instead of the injury of reperfusion itself. Therefore, removing fibrin and fibrinogen deposition from the microvasculature can be a suitable target for achieving better myocardial perfusion.
In our pilot study, it had been demonstrated that ICSK administration immediately after primary PCI significantly improves microvascular perfusion. Nevertheless, the sample size of the study was not enough to evaluate the effect of this mode of therapy on long-term infarct size, ventricular volumes, and LV function.
In the current study, it has been shown that adjunctive ICSK therapy prevents LV dilation, preserves systolic function, and decreases long-term LV infarct size by 31% compared with conventional primary PCI. The absolute difference in infarct size was 10% between the groups. No other study on adjunctive therapy to primary PCI has reported this amount of benefit. Because the relation between infarct size and mortality is well known, a 31% relative reduction of infarct size promises a substantial prognostic benefit. Furthermore, significantly smaller LV volumes and higher ejection fractions were observed in the ICSK group in the long-term follow-up.
This is a relatively small, single-center study. Although the procedural recordings and all follow-up parameters were analyzed by blinded investigators, the study drug was administered in an open-label fashion. Finally, none of the methods using for evaluating the efficacy of adjunctive therapies to primary PCI is precise. Inherent limitations of the methods used in this study have to be taken into consideration in the interpretation of the results.
Low-dose ICSK administered immediately after primary PCI improves microvascular perfusion, decreases long-term infarct size, and improves LV volumes and function. These positive effects on main determinants promise parallel changes in long-term clinical outcomes.
The authors thank Prof. Rian Dişçi for his valuable assistance with the statistical analyses and Pınar Umman for revision of the paper.
Supported by grants from Istanbul University (BYP-637/03032005) and the Turkish Academy of Sciences.
- Abbreviations and Acronyms
- corrected Thrombolysis In Myocardial Infarction frame count
- intracoronary streptokinase
- infarct-related artery
- left ventricular
- myocardial blush grade
- percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- single-photon emission computed tomography
- Thrombolysis In Myocardial Infarction
- Received January 20, 2009.
- Revision received April 20, 2009.
- Accepted April 20, 2009.
- American College of Cardiology Foundation
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