a CardioThoracic Department, University of Pisa, Ospedale Cisanello, Pisa, Italy
b CNR, Clinical Physiology Institute, Pisa, Italy
c Oncology Department, University of Pisa, Ospedale Santa Chiara, Pisa, Italy
Received April 30, 2003; accepted May 8, 2003 * Correspondence: Anna S. Petronio, MD, CardioThoracic Department, University of Pisa, Ospedale Cisanello, Via Paradisa, 2, 56124 Pisa, Italy
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Abstract |
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Methods and results Thirty-one patients (27 males; age 3976 years) with first, acute MI (<6 h after onset) were randomized to receive either abciximab+primary PTCA (n=17) or primary PTCA alone (n=14). Baseline characteristics of the two groups were similar. Myocardial reperfusion was studied shortly after PTCA by corrected TIMI frame count (cTFC) and intracoronary myocardial contrast echocardiography (MCE), after 48 h by intravenous MCE using intermittent, harmonic power Doppler, and after 1 month by intravenous MCE and 99 mTc-tetrofosmin SPECT. The patients treated with abciximab showed a shorter cTFC (23±4 vs 30±9 frames; P<0.05), a more preserved microvascular integrity shortly after PTCA (77% vs 55%; P<0.01), after 48 h (86% vs 50%; P<0.005) and at 1-month follow-up (86% vs 54% by MCE, P<0.001, and 68% vs 60% by SPECT, P<0.005) than patients treated with PTCA alone. Abciximab patients also showed a better recovery of LV function, as demonstrated by greater reduction in wall motion score index (1.4±0.3 vs 1.5±0.2; P<0.05) and increase in LV ejection fraction (53±7% vs 48±5%; P<0.001).
Conclusions Abciximab improves microvascular perfusion and LV functional recovery in primary PTCA.
Key Words: Contrast echocardiography primary PTCA myocardial infarction platelet inhibitors coronary microcirculation
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Introduction |
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To preserve microvascular integrity in the infarct related myocardium, new therapeutic strategies have been proposed in adjunction to primary PTCA. Specifically, verapamil has been shown to reduce TIMI II flow probably by reversing coronary microvascular spasm,15 and adenosine has recently been demonstrated to improve myocardial reperfusion by its multifactorial action on leukocytes, platelets and other mediators.16 Due to the role of platelet aggregation and possible thrombus embolism onthe no-reflow phenomenon, glycoprotein IIb/IIIa receptor antagonists have been postulated asone of these adjunctive treatments. In particular, abciximab has been shown to enhance coronary blood flow in primary PTCA patients and to improve functional recovery by its action on platelets,leukocytes and probably on micro embolisms.1720 With these considerations in mind, this study was undertaken to investigate the effect of abciximab on microvascular integrity and LV functionalrecovery in patients with acute MI treated byprimary PTCA.
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Methods |
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Exclusion criteria were: previous MI, previous coronary artery bypass graft surgery, cardiogenic shock, multivessel coronary disease or >50% left main stenosis, significant valvular disease, age more than 80 years and any counterindication to platelet glycoprotein IIb/IIIa receptor antagonists or primary PTCA.
The study complies with the Declaration ofHelsinki. The protocol was approved by the Ethical Committee of the University of Pisa. All patients gave formal written consent before the procedure.
Study protocol
Before PTCA, patients were treated with aspirin, intravenous nitrates and a 5000 IU bolus of unfractionated heparin. Coronary arteriography was performed by the femoral approach. Immediately after coronary arteriography patients, if eligible, were randomized to receive either abciximabplus heparin (group A) or only heparin (group B). Group A patients received a bolus of abciximab (0.25mg.kg1) followed by a 12-h infusion(0.125µg.min1); during PTCA an adjunctive bolus of heparin was administered according to body weight (70 IU.kg1) and to ACT (Activated dating time) monitoring (included between 250 and 300 s). After the procedure no more heparin was given and the activated partial thromboplastin time (aPTT) was monitored for the following 12 h. Group B patients were treated only with a heparin bolus during PTCA (according to body weight and ACT between 250 and 300 s), followed by a continuous intravenous infusion of unfractionated heparin (10IU.kg/h1) for 24 h; the infusion was titrated every 6 h as needed to maintain aPTT between 50 and 70 s. All patients received a coronary stent (Multilink, NIR or GFX) and were treated withaspirin 300 mg daily plus ticlopidine 250 mg twice a day, reduced to 250 mg daily after 1 week. Beta-blockers and angiotensin-converting enzyme inhibitors, if not contraindicated and well tolerated, were routinely administered to all patients independently of randomization. The success of primary PTCA was defined as achievement of a residual stenosis <30% of diameter reduction with TIMIflow grade 3, together with disappearance of ST elevation and chest pain.
Immediately after PTCA, a 2D echocardiogram and intracoronary myocardial contrast study were performed. After 48 h a transthoracic 2D echocardiogram with intravenous contrast administration and harmonic power Doppler imaging (HPDI) was performed. At 1-month follow-up all patients underwent a 2D echo with intravenous contrast administration and a stress and rest 99 mTc-tetrafosmin SPECT.
Clinical and metabolic data
All patients were screened for ECG changes; to assess the extent of microvascular reperfusion,serial ST-segment analysis on a 12-lead ECG recording just before and 30 to 60 min after coronary intervention was done by one observer blinded to clinical data. A decline of ST-segment elevationexceeding 50% of initial valuewas the electrocardiographic criterion of microvascular reperfusion.21 Creatinine kinase (CPK) and creatinine-kinase-MB (CK-MB) values were assessed every 6 h during the first day and then every day before discharge, unless clinical events suggested further measurements. Adverse clinical events (including death, ventricular arrhythmias, re-infarction, recurrent angina, target lesion revascularization and heart failure) were evaluated during hospital stay and at the 30-day follow-up.
Bleeding was defined according to the criteria of the Thrombolysis in Myocardial Infarction trial22; major bleeding was defined as a decrease in the haemoglobin level of 5g.dl1, intracranial haemorrhage or cardiac tamponade, and minor bleeding was defined as a decrease in the haemoglobinlevel of more than 3g.dl1from an identified site, spontaneous gross haematuria, haematemesis, haemoptysis or puncture site bleeding.
Echocardiographic and echo contrast follow-up
2D echo and intracoronary MCE
At the end of PTCA, a radiographic non ionic, low osmolar contrast medium (iopromide), the same as utilized for angiography, was sonicated to generate microbubbles according to a standardized protocol23; these microbubbles have a mean diameter of 8 µm.24 Eight microlitres of the sonicated medium were manually injected in the coronary arteryrelated to the infarcted area. After the injection, the catheter was removed from the coronaryostium and any contrast agent remaining in the catheter was withdrawn. Echocardiographic images were obtained by using a commercial scanner (Sonos 5500, Agilent Technologies, USA), equipped with a 2.53.75 MHz transducer. With the patient lying down in the supine position the probe was oriented to obtain apical four-, five- and two-chamber views of the heart. Before contrastinjection, the echocardiographic images wererecorded to identify the asynergic area and to quantify both LV ejection fraction (EF) and wall motion score index (WMSI); after contrast administration the images were recorded to document myocardial enhancement until its disappearance. Gain setting controls were maintainedconstant during data acquisition; the imageswere stored on a Super VHS videotape for further evaluation.
Forty-eight h and 1-month 2D echo and MCE
After 48 h each patient underwent myocardial contrast echocardiography using Levovist (Schering AG, Berlin, Germany), a galactose-based agent containing microbubbles with an average diameter of34 µm. The safety of Levovist and its lack of adverse effects on haemodynamics, LV function, and pulmonary gas exchange have been demonstrated.25 Levovist powder (4 g) was reconstituted by adding 8 ml of sterile water to give a concentration of 400 mg.ml1. It was administered intravenously as a slow bolus (first 2 ml over a period of 4 s), followed by a slow infusion (remaining 8 ml over a period of 2 min). Contrast agent injection was followed by a 5 ml saline flush.
Harmonic power Doppler was performed with the same scanner and with a transducer transmitting and receiving at a mean frequency of 1.8 and 3.6 MHz, respectively; the dynamic range of this system is 40 dB. The mechanical index was set as high as possible to favour microbubble resonance and destruction. Images were triggered to thepeak of the T wave, every fourth cardiac cycle. End-systolic triggering was chosen because the myocardial wall segments are thicker and LV cavity size smaller, resulting in less contrast attenuation. To avoid artifacts related to cardiac motion the endsystolic triggering was carefully tuned. Theacquisition of MCE images started just before contrast injection and was continued until contrast effect in the myocardium had dissipated. Echoimages were acquired in the apical views utilized during the first registration with intracoronary MCE.
Ultrasound system gains were optimized at the beginning of the study and held constant during subsequent image acquisitions. To minimize the misinterpretation of artifacts, HPDI images were displayed on a split screen, in which the first ultrasound exposure results in microbubble stimulation and the second in bubble destruction. The images were stored digitally on a magneto optical disk and on super VHS videotape.
Single photon emission computed tomography
All patients underwent a myocardial perfusion SPECT study according to a stress and rest protocol. About 1 h after the i.v. administration of 740 MBq of 99Tc-Tetrofosmin under resting conditions, SPECT images were acquired by using a dual detector gamma camera (Optima NT ELGEMS) equipped with LEHR (low emission high resolution) collimators. Thirty-two views of 60 s each, over an orbit of 180°, were acquired from the 45° RAO (right anterior oblique) to the 45° LPO (left posterior oblique) projection on a matrix of 64x64 pixels (6 mm pixel size). The energy window used was 20% centred on the 140 KeV photo peak of 99Tc. Tomographic reconstruction was performed with filtered backprojection using a low pass Butterworth filter with a cut-off frequency of 0.4 cycles/cm and order 10. No attenuation or scatter correction was used. Transaxial slices (1 pixel thick) were then reoriented along the vertical and horizontal long axes and the short axis of the left ventricle.
Image interpretation
The corrected TIMI frame count (cTFC) was calculated for the infarct-related artery according to the technique described by Gibson and coworkers26 after the first balloon inflation and after stent deployment.
In echocardiographic analysis, the LV myocardium was divided according to a 16-segment model; the wall motion of each segment was scored according to a 5-point scale, where 1 is normal, 2 is hypokinetic, 3 is akinetic, 4 is dyskinetic and 5 is aneurismal.27 The WMSI was obtained averaging the scores of the visualized LV segments. In eachpatient left ventricular ejection fraction (LVEF) was calculated by using the modified Simpsons rule.
Myocardial contrast enhancement was assessed by dividing LV myocardium according to the same 16-segment model and assigning to each segment a score of 0 (no enhancement), 0.5 (heterogeneous or subepicardial enhancement) or 1 (homogeneous contrast effect). For each patient a perfusion score index was calculated by averaging the contrast scores of the segments within the area at risk, defined as the LV area showing wall motion abnormalities at the first echocardiographic study.28 The analysis of 2D echocardiograms, of intracoronary and intravenous contrast studies was performed by two independent observers, blinded to the clinical history and SPECT data, and twice by the same observer.
The reading of 2D echocardiograms, of intracoronary and intravenous contrast studies wasperformed separately for every patient.
Horizontal and vertical long-axis views by SPECT imaging were also interpreted by two independent observers. All the observers were blind to the treatment. For semi-quantitative analysis, short axis slices from the first apical to the last basal slice were used for generating a two-dimensional volume-weighted polar map. This map was divided into 16 segments, to be as close as possible to the echocardiographic analysis. The segment with the highest mean tracer uptake was then normalized to 100% and the activity within the other segments was expressed as a percentage of peak activity. According to other authors29,30 segmental 99 mTc-tetrofosmin activity was classified as mild tomoderately abnormal if it was <75% and >55% of the peak value and as severely abnormal if it was <55% of the peak value.
Statistical analysis
Categorical data are presented as absolute values and percentages, whereas continuous data are summarized as mean value±SD. Chi-squared and Fishers exact tests were used for comparison of categorical variables as appropriate. Comparisonof continuous variables was performed by means of Students t-test or Wilcoxon rank-sum test, asappropriate. Linear regression analysis was performed to identify correlation between cTFCand MCE score. P values <0.05 were considered statistically significant.
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Results |
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The interventional procedures were all successful and all the stents were successfully deployed. As shown in Fig. 1, the cTFC after first balloon inflation was similar in both groups (33±12 in group A vs 37±9 frames in group B, P=0.24); after stentdeployment cTFC decreased, and reached lower values in abciximab treated patients (23±4 in group A vs 30±9 frames in group B, P<0.05).
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On both SPECT and contrast echocardiography interpretation, the two observers were in agreement in 92% of the segments analysed; the intra-observer agreement was 93%. Scoring both myocardial contrast enhancement and tetrofosmin activity on a 3-point scale, the two methods were in agreement in 48% of segments. Scoring myocardial perfusion as normal or abnormal, an agreement was present in 56% of segments (k=0.26).
LV functional recovery
Immediately after PTCA, global and regional LV functions were similar in the two groups. At 30-day follow-up, LV function improved in both groups, but to a greater extent in group A than B. Specifically, the WMSI of group A patients decreased from 1.78±0.27 to 1.36±0.30 (P<0.001), while that of group B decreased from 1.75±0.20 to 1.52±0.20 (P<0.05, Fig. 5, top panel). Accordingly, LVEF improved in both groups, being an increment higher in group A (from 48±6% to 53±7%; P<0.001) than in group B patients (from 46±4% to 48±5%; P=0.17).
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Discussion |
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Microvascular integrity after primary PTCA
The goal of treatment in acute MI is not onlyrecanalization of the epicardial infarct relatedartery, but also adequate reperfusion of the coronary microcirculation.31 Even patients with good contrast runoff (TIMI 3 flow) can have different outcome and LV functional recovery in relation to post-reperfusion microvascular damage.11,12 This reperfusion injury is a multifactorial phenomenon involving platelet aggregation, leukocyte plugging, endothelial dysfunction and coronary microembolism.18,19 Some of these mechanisms could be prevented by new therapies, adjunctive to primary PTCA. In this study we evaluated the influence of abciximab on reperfusion injury in a highly selected and homogeneous patient population.
Diagnostic tools to identify microvascular damage
Many diagnostic indicators have been proposed to investigate coronary microcirculation after reperfusion. Resolution of ST-segment elevation is a non-invasive, inexpensive predictor of mortality inhuge patient populations,32 but it lacks sensitivity. Angiographic parameters such as cTFC and angiographic blush score33,34 can risk-stratify patients with acute MI, although they are invasive and not easily repeatable. Doppler derived coronary flow velocity reserve relates to recovery of myocardial contractile function35 and the wave forms arepredictive of functional recovery36; however, this technique is again invasive. MCE provides direct and immediate information on coronary micro-circulation, is able to detect the changes occurring after reperfusion and to unmask perfusion abnormalities even in patients with TIMI 3 flow1014; however, MCE is limited as far as feasibility and artifacts are concerned. Nuclear perfusion is accurate, but rarely utilized in the acute setting. For these reasons, we investigated the effects of abciximab on myocardial perfusion with an integrated approach using cTFC, MCE and SPECT.
Therapeutic effects on no-reflow
A variety of therapies, adjunctive to PTCA, have been proposed to improve reperfusion in acute MI. Specifically, verapamil, adenosine and nicorandil have been shown to reduce the no-reflowphenomenon in man.15,16,37 More recently, platelet glycoprotein IIb/IIIa inhibitors have been utilized to improve outcome of patients with acute MI treated with PTCA. Although the impact of abciximab on acute coronary syndromes has been demonstrated in several studies,38,39 the real benefit of thisdrug during primary PTCA and stenting is stilldebated.40,41 Abciximab is supposed to preventreocclusion of the epicardial infarct related artery and to reduce reperfusion injury by interfering with platelet aggregates, leukocyte plugging and reducing microembolism due to stent deployment. The recent French experience in the ADMIRAL trial has proven that abciximab is able to improve myocardial perfusion after primary PTCA with stent deployment especially if administered prior to the procedure, while the most recent results of the CADILLAC trial underline the importance of stents in primary PTCA without confirming the advantage of platelet inhibitor therapy. However, in this last trial a crossover to abciximab was allowed when no reflow occurred. Neumann and coworkers17 showed an increase in coronary peak flow velocity in AMI patients treated with abciximab but did notobserve changes in coronary flow reserve, suggesting a higher number of functional segments in treated patients. We evaluated the effect of this adjunctive treatment on reperfusion and wefocused our attention mainly on coronary microcirculation and LV functional recovery. The population was highly selected, and patients with previous infarction or receiving thrombolysis before PTCA were not included. Furthermore, a high percentage of anterior infarction patients was enrolled, and a homogeneous interventional procedure was carried out: only one vessel was treatable and no devices were used except for stent deployment.
It has been suggested that stents are able to improve epicardial flow and to reduce the risk of acute and late restenosis, but to some extent they are responsible for the no-reflow phenomenonby microembolism of the plaque thrombus. We analysed whether this event could be reduced by abciximab pretreatment. After balloon dilatation all subjects showed a similar cTFC; however, after stenting, patients treated with abciximab had a significantly lower cTFC than the control group (Fig. 2). This observation underlines the role of the platelet inhibitor in reducing microembolization caused by stent deployment, thus preserving microvascular integrity (demonstrated by both MCE and SPECT) and favouring LV functional recovery.
Study limitations
A major limitation of this study is related to the small number of patients enrolled. Intracoronary MCE in patient with acute MI is limited by the short time window for data collection, the acute clinical setting and organization problems. Furthermore, the acoustic window is often limited in patients lying on the cardiac catheterization table. Due to the above limitations, contrast echo studies in acute infarction rarely involve a huge patient population. The method used for the assessment of perfusion by MCE immediately after PTCA, after48 h and at 1 month was different. However, the accuracy of intracoronary MCE has been demonstrated in several studies, and the substantial agreement between intracoronary and intravenous MCE in AMI patients has been recently underlined.42 Additionally, contrast echo images were not quantified and a fixed triggering interval was utilized.43 These limitations could be overcome by using new technologies based on real time myocardial perfusion,44,45 that were not available at the time of the study. Collateral circulation was not evaluated in this study, the sonicated radiographic contrast medium was injected only in the infarct related artery. Collateral circulation was also not assessable by coronary arteriography, as no patient showed an angiographic Rentrop score 1. Finally, although substantial agreement between the different techniques existed when each of them acted as its own control, the agreement between myocardial contrast enhancement and SPECT datawas limited. The ability of myocardial contrast enhancement to predict tracer uptake varies widely in the different studies, ranging from a limited46,47 to a good agreement.4851 This study shows a limited correlation between contrast echocardiography and SPECT. This discrepancy is probably due to the intrinsic differences between the two techniques, to the difficulties in comparing various perfusion territories by these twoapproaches or in different cut-off values utilized to define reduced myocardial tracer uptake in the different studies.
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Conclusions |
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References |
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