Does coronary angioplasty after timely thrombolysis improve microvascular perfusion and left ventricular function after acute myocardial infarction?

Does coronary angioplasty after timely thrombolysis improve microvascular perfusion and left ventricular function after acute myocardial infarction? Luciano Agati, MD,a Stefania Funaro, MD,b Mariapina Madonna, MD,a Gennaro Sardella, MD, FACC, FESC,a Barbara Garramone, MD,c and Leonarda Galiuto, MD, PhD, FACCc Rome, and Campobasso, Italy

Background Recent data show that percutaneous coronary intervention (PCI) in patients with stable postthrombolytic ST-segment elevation myocardial infarction (STEMI) is better than no PCI or ischemia-guided PCI. These results still have to find a pathophysiologic explanation. We hypothesized that complete mechanical recanalization of infarct-related artery improves clinical benefits of thrombolysis as a result of more preserved and better perfused coronary microcirculation. To test this hypothesis, we studied a selected STEMI population presenting very early after symptom onset in whom successful infarctrelated artery reperfusion was obtained by thrombolysis followed or not by elective PCI within 24 hours, and we compared these 2 groups with those underwent primary PCI. Methods This study analyzed 96 patients with STEMI randomized within 3 hours from symptom onset to primary PCI (group A, n = 36), tenecteplase followed within 24 hours by PCI (group B, n = 30), or to tenecteplase alone (group C, n = 30). Microvascular perfusion was assessed by myocardial contrast echocardiography. Regional contrast score, endocardial length and area of contrast defect on day 2 (T1) and at predischarge (T2), left ventricular end-diastolic volume, regional wall motion score, extent of wall motion abnormalities, and ejection fraction at T1, T2, and at 3 months’ follow-up were calculated. Results

Baseline clinical and angiographic characteristics were not statistically different between groups. The extent of microvascular damage and of myocardial salvage was similar in primary PCI–treated or in invasively treated patients after lytic administration. Conversely, group C patients, although treated very early with fibrinolytic therapy, showed higher extent of microvascular damage and infarct size and a more depressed left ventricular function after reperfusion and at follow-up.

Conclusions

Our data suggest that early PCI after lysis is more effective in preserving myocardial perfusion and function than lysis alone and may be a helpful alternative when primary PCI is not available. (Am Heart J 2007;154:15127.)

Recent survey showed that b25% of hospitals in the United States and b10% of European centers have the capability of performing primary percutaneous coronary intervention (PCI)1; thus, at present emergency PCI is only available on an average for 15% to 20% of patients with ST-segment elevation myocardial infarction (STEMI) in western countries. Therefore, fibrinolytic therapy is still the fastest and best accessible reperfusion treatment for most patients with STEMI.2

From the aDepartment of Cardiology, bLa SapienzaQ University, Rome, Italy, bDepartment of Cardiology, Catholic University, Campobasso, Italy, and cInstitute of Cardiology, Catholic University, Rome, Italy. Submitted October 12, 2006; accepted March 19, 2007. Reprint requests: Luciano Agati, MD, Department of Cardiology, bLa SapienzaQ University of Rome, Rome, Italy. E-mail: [email protected] 0002-8703/$ - see front matter n 2007, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2007.03.028

Despite successful infarct-related artery (IRA) reopening demonstrated by clinical signs of reperfusion, beneficial effects of fibrinolysis for mortality can still be improved by complete coronary recanalization obtained by early elective angioplasty.3 Although convincing and consistently reproduced in several clinical trials,4-11 these results still have to find a pathophysiologic explanation. We hypothesized that complete mechanical recanalization of IRA improves clinical benefits of thrombolysis as a result of more preserved and better perfused coronary microcirculation. To test this hypothesis, we studied a selected STEMI population presenting very early after symptom onset in whom successful IRA reperfusion was obtained by thrombolysis followed or not by elective PCI within 24 hours, and we compared these 2 groups with those who underwent primary PCI. Postischemic microvascular damage was assessed and quantitated by myocardial contrast echocardiography (MCE).

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Methods Study population From December 2004 and November 2005, 104 consecutive patients with first STEMI were randomized in an open-label fashion to primary PCI (group A, n = 38), thrombolysis followed within 24 hours by PCI (group B, n = 32), or thrombolysis alone (group C, n = 34). Patients with STEMI were eligible for this study if they presented in the emergency department within 3 hours of symptom onset. Patients who underwent revascularization procedure as a result of failed thrombolysis, early reinfarction, or ischemia after the initial treatment (lysis or PCI) were excluded. Patients aged z80 years; with a history of previous myocardial infarction, cardiomyopathy, or coronary artery bypass graft surgery; contraindication to platelet glycoprotein IIb/IIIa receptor antagonists, primary PCI, or lysis; or in cardiogenic shock were also excluded. The local ethic committees approved the study protocol, and all patients gave informed written consent before enrolment in the study.

Study protocol At randomization, all patients received aspirin and subcutaneous enoxaparin (1 mg/kg). In patients assigned to conservative treatment, enoxaparin was repeated every 12 hours up to 7 days after lysis, and 100 mg aspirin once a day was given indefinitely. No further enoxaparin was given to patients assigned to mechanical revascularization. Patients allocated to primary PCI received IRA stenting using a standard procedure. Patients randomized to the other 2 arms received a full dose of tenecteplase (TNK), followed only in group B by IRA stenting within 24 hours from symptom onset. Patients allocated to interventional strategy (groups A and B) received abciximab immediately before the interventional procedure (0.25 mg/kg body weight), followed by a 12-hour infusion at a rate of 0.125 Ag/(kgd min) and loading dose of clopidogrel 300 mg. After the procedure, 75 mg/d clopidogrel was prescribed for 6 months and 100 mg aspirin once a day indefinitely. On day 2 after hospital admission (T1), 2-dimensional echocardiogram (2DE) was performed and was repeated at predischarge (T2). Followup 2DE was scheduled after 3 months (T3).

Quantitative analysis was performed on MCE images after coronary reflow and at predischarge using parametric Qontrast Software (Bracco Imaging, Milan, Italy), as previously described.12,13 In brief, from parametric images, the area of contrast defect (CDA) was calculated using 4-color map segmentation; the blue area, corresponding to the largest clearly demarcated contrast defect, was manually traced. Contrast defect area was expressed as the percentage of the total LV area (CDA%) (Figure 1). From native MCE images, the length of endocardial border corresponding to the segment with contrast defect (CDL) was also measured in 2-,4-, and 3-chamber views. The sum of endocardial borders length measurements defined the size of perfusion defect. The following formula was used to assess the relative CDL (CDL%): (total residual CDL after reperfusion) / (total length of endocardial border)  100. All images were independently analyzed by 2 experienced observers (LA for MCE data, SF for echocardiographic data) blinded to the clinical data and to each other’s results. Final data were the average of 3 measurements performed by a single operator. Our interobserver and intraobserver variability for quantitative analysis of perfusion defect in patients with AMI has been previously reported.12-17

Echocardiographic analysis The 2DE images were obtained by a commercially available echocardiographic equipment to assess the impact of reperfusion strategies on LV function. For the wall motion analysis, a 17-segment model was used. A semiquantitative scoring system (1 normal; 2, hypokinesis; 3, akinesis; 4, dyskinesis) was used to analyze each study. Regional LV wall motion score index (RWMSI) was calculated for each examination by dividing the total wall motion score of dysfunctional segments by the number of dysfunctional segments analyzed. Thus, the RWMSI at T2 and at follow-up referred to dysfunctional segments at baseline. A percentage of the extent of wall motion abnormalities (WMA%), as an index of the ischemic damage, was obtained by dividing the number of dysfunctioning segments by the total number of segments evaluated. Left ventricular end-diastolic volume (LVEDV), end-systolic volume, and ejection fraction (LVEF) were also calculated at each control.

Primary end point

Coronary artery cineangiography

The primary end point of this study was to assess the effects of early PCI after successful lysis on the residual extent of microvascular damage. Microvascular perfusion was assessed by real-time MCE using continuous infusion of Sonovue (Bracco Imaging), as previously described.12 For qualitative analysis of myocardial perfusion, each initially dysfunctional left ventricular (LV) segment was graded using MCE during simultaneously performed 2DE, 4-, 2-, and 3-chamber apical views. Poor or no opacification was defined as delayed, low, or absent contrast enhancement in the evaluated segment when compared with adjacent segments with adequate opacification. A 17-segment LV model was used to assign the following contrast scores: 1, homogeneous enhancement; 2, patchy enhancement; 3, no enhancement. Regional contrast score index (RCSI) was calculated by dividing the sum of contrast scores for each dysfunctional segment by the number of dysfunctional segments analyzed. In case of disagreement over scoring, a consensus was reached after open discussion.

Coronary angiography and angioplasty were performed by standard procedure and equipment. The antegrade radiocontrast flow through the IRA was determined on coronary angiography using the TIMI criteria. Interventional success was defined as stent-implanted residual stenosis of b15% and a TIMI grade 3 flow after stent implantation. Coronary angiography and angioplasty data were collected and analyzed by 3 experienced observers. Consensus on procedural success, TIMI grade, and extent of coronary artery disease was reached in all cases.

Statistical analysis All data were analyzed with Stasoft Statistica software package (version 6.0, Stata Corp, College Station, TX). Results are given as mean F 1 SD. Continuous and categorical data were compared using 2-tailed Student t test and conventional m2 tests, respectively. Changes over time of continuous variables and comparison between groups were analyzed by

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Figure 1

Example of method used to assess CDA from parametric imaging in a patient with acute lateral myocardial infarction. The area of blue zone corresponding to severe reduction in myocardial perfusion was calculated and expressed as the percentage of total LV area.

Table I. Baseline (day 2) clinical and angiographic characteristics of patients with AMI undergoing primary PCI (group A), early PCI after fibrinolysis (group B), or fibrinolysis alone (group C) Primary PCI (n = 36) Mean age (y) Male Hypertension Cholesterol (mg/dL) Current smoker Diabetes Time to randomization (min) Time to first treatment* (min) Killip class N1 Peak CK (IU/L) Multivessel disease Anterior MI TIMI 3 flow before PCI TIMI 3 flow after PCI

61 30 31 198 23 7 98 132 12 1210 14 26 6 30

F6 (87) (86) F 23 (63) (19) (64-158) (78-177) (33) F 570 (38) (72) (16) (83)

Lysis + PCI (n = 30)

Fibrinolysis (n = 30)

59 25 26 202 17 6 103 118 11 1119 11 24 20 26

57 26 24 210 19 5 108 129 11 1224 10 22 – –

F7 (83) (86) F 34 (56) (20) (62-165) (72-170) (36) F 830 (36) (80) (66) (86)

F7 (86) (80) F 27 (63) (16) (66-160) (74-167) (36) F 650 (33) (73)

P NS NS NS NS NS NS NS NS NS NS NS NS .015 NS

Data presented are mean value F SD or number (percentage). NS, Not significant; CK, creatine kinase; MI, myocardial infarction. *Time from symptoms onset to primary PCI (Group A) or to Fibrinolysis (Group B and C).

2-way analysis of variance for repeated measures and Scheffe` F test. Linear regression analysis was used to assess the correlation between LVEF and RWMSI at follow-up and CDL% on admission. Differences for single comparisons were considered significant at P b .05.

Results Baseline demographic, clinical, and angiographic data Of the 104 patients with STEMI admitted in the study during the enrolment period, 8 (2 group A, 2 group B, and 4 group C) underwent revascularization procedure during hospital stay because of unstable clinical conditions and were excluded. The remaining 96 patients were enrolled in the study. The culprit lesion was in the left anterior descending coronary artery in 62 (64%) of 96, in the left circumflex coronary artery in 10 (10%),

and in the right coronary artery in 24 (25%). Multivessel disease was present in 35 patients (36%). No patient had major bleeding complications, whereas minor bleeding complications (at access site) occurred in 4 group B patients. All patients were maintained on angiotensinconverting enzyme inhibitors and h-blockers throughout hospital stay and at discharge. The dosage was at the discretion of the physician in charge of the patient. Table I shows clinical and angiographic characteristics of enrolled patients at T1. Time from symptom onset to first treatment was rapid in all. There was no significant difference in age, sex, risk factors, Killip class on admission, prevalence of multivessel coronary artery disease, anterior infarct site, and peak creatine kinase between groups. No difference in TIMI grade 3 flow after PCI was found in patients allocated to invasive strategy (groups A and B). In group B patients, PCI time after fibrinolysis was 20 F 2 hours; restora-

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Table II. Myocardial contrast echocardiography parameters Primary PCI RCSI CDL% CDA%

Day 2 Predischarge Day 2 Predischarge Day 2 Predischarge

1.9 1.7 17 14 13 10

F F F F F F

0.6 0.5 16 17 11 10

Lysis + PCI 1.7 F 1.6 F 13 F 9F 12 F 9F

0.7 0.6 16 12 9 7

Fibrinolysis 2.1 2.0 23 27 20 22

F F F F F F

0.4 0.5 29 27 19 20

P* .007 .000 .061 .000 .000 .000

*Overall statistical significance between groups at each stage.

Table III. Echocardiographic parameters Primary PCI LVEDV

WMA%

RWMSI

LVEF%

Day 2 Predischarge Follow-up Day 2 Predischarge Follow-up Day 2 Predischarge Follow-up Day 2 Predischarge Follow-up

108 109 110 38 32 30 2.6 2.2 2.0 47 48 49

F F F F F F F F F F F F

26 26 31 20 20 23 0.6 0.7 0.7 9 10 10

Lysis + PCI 102 F 33 103 F 34 111 F 50 34 F 18 27 F 22 24 F 19 2.8 F 0.5 2.44 F 1 2.1 F 0.8 47 F 8 48 F 9 51 F 11

Fibrinolysis 123 128 136 51 48 47 2.8 2.6 2.6 38 39 40

F F F F F F F F F F F F

26 57 57 28 33 36 0.2 0.6 1 11 14 17

P* .02 .007 .010 .001 .000 .003 .118 .383 .061 .000 .000 .000

*Overall statistical significance between groups at each stage.

tion of TIMI grade 3 flow was achieved in 66% of patients after lysis and in 86% after early PCI, but persistent IRA occlusion was never observed before the invasive procedure.

Influence of reperfusion strategies on LV function and tissue-level perfusion The T1-MCE was performed 26 F 4 hours from hospital admission and the T2-MCE at 6 F 2 days from admission. The T3-2DE control was repeated at 11 F 3 weeks. All 96 patients underwent initial and predischarge MCE and follow-up echocardiogram control. Adequate MCE was achieved in 95% of LV segments (1565 of 1632) and in 97% of the dysfunctional segments assessed for the study. All artifacts were excluded from analysis. More than half of the artifacts preventing assessment of MCE occurred in the basal inferoposterior (16%), lateral (11%), and anterior (28%) walls. Temporal changes in tissue level perfusion and LV function are summarized in Tables II and III. Initial extent of microvascular damage (RCSI, CDL%, and CDA%), LVEDV, LVEF, and infarct size (RWMSI and WMA%) were similar in patients treated with primary PCI or with early PCI after lysis, whereas higher extent of microvascular damage ( P = .005 and P = .01, respectively) and infarct size ( P = .006 and P = .001, respectively) and a more depressed global LV function

after reperfusion ( P = .00002 and P = .0002, respectively) were found in patients treated with lysis alone compared with those in groups A and B. At least 1 segment with contrast defect within the initial dysfunctioning area was detected in 26 (72%) of 36 group A, in 20 (66%) of 30 group B, and in 25 (83%) of 30 group C patients. Predischarge examination found no statistical differences between groups A and B, whereas significant difference was observed in group C for tissue-level perfusion ( P = .006 and P = .001, respectively), global LV function ( P = .0001 and P = .0008, respectively), and definitive infarct size ( P = .002 and P = .0005, respectively). These differences were maintained at follow-up. In particular, in the first 2 groups, a reduction in the extent of CDL% was observed from day 1 to predischarge. Accordingly, in groups A and B, a significant reduction between T1 and T2 in RWMSI ( P = .001 and P = .001, respectively) and WMA% ( P = .05 and P = .01, respectively) occurred. This functional improvement was confirmed at follow-up. Conversely, in patients treated with TNK alone, no significant changes in the extent of microvascular damage (RCSI, CDL%, and CDA%) were observed at predischarge. Similarly, infarct size (RWMSI and WMA%), LVEDV, and LVEF did not change at predischarge or at follow-up. A similar slight reduction of the number of patients with at

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Figure 2

Contrast-enhanced apical 4-chamber views in patients with AMI treated with primary PCI (A and B) or with early PCI after lysis (C and D). Similar extent of tissue-level perfusion was detected on day 1 after reperfusion (A and C). At predischarge (B and D), a similar improvement of tissuelevel perfusion was detected.

least 1 segment with contrast defect was observed at predischarge in groups on invasive strategy (65% in group A and 63% in group B), whereas it remained the same in group C (83%). In the entire study population, a close correlation was found between CDL% on admission, and LVEF and RWMSI observed at follow-up (CDL%T1-LVEF%T3: r = 0.65, P = .00000005; CDL%T1-RWMSIT3: r = 0.68, P = .000000001).

Discussion The main finding of the present study is that the efficacy of thrombolysis, even performed very early, is improved by subsequent mechanical intervention. This combined strategy is as effective as primary PCI is in restoring tissue level perfusion and improving LV function after acute myocardial infaction (AMI), and it may be a helpful alternative when emergency PCI is not available (Figure 2).

Previous studies There is convincing data from several trials showing that PCI in patients with stable postthrombolytic STEMI

is better than no PCI or ischemia-guided PCI.4-10 A recent meta-analysis11 confirms that early stent-PCI after fibrinolysis is associated with a better survival and a significant reduction of death compared with a delayed or ischemia-guided PCI strategy. We have previously showed that primary PCI is more effective than lysis in preserving microvascular flow15; however, no data are available on the efficacy on tissuelevel perfusion of early PCI after successful lysis compared with primary PCI and timely lysis alone. In the CAPTIM study, prehospital lysis and systematic transfer to an interventional center were associated with excellent clinical results9 similar to those obtained by primary PCI. In the very recent WEST and GRACIA-2 trials,10,18 strategy of timely pharmacologic therapy followed by coronary intervention is not different for clinical outcome and myocardial salvage from primary PCI. In the present article, we showed a lower extent of microvascular damage and infarct size after reperfusion and at 3 months’ follow-up in patients treated with primary PCI or invasively treated after lytic administration compared with the subset of patients early treated with fibrinolytic therapy alone. Similar data have been reported in the SWEDES trial, showing a better epicar-

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dial flow after primary PCI compared even with prehospital lysis.19 Unlike previous studies carried out before the use of stents and modern antithrombotic and antiplatelet agents, the incidence of bleeding complications in the present study was very low, as previously shown.4–10 The ASSENT 4 trial was recently halted secondary to increased mortality in the facilitated PCI arm, but in this study PCI was always performed within 3 hours from lysis.20 The combination of full-dose thrombolysis with pharmacotherapy associated with immediate PCI may increase the risk of bleeding, whereas the routine but deferred invasive strategy—17 hours after lysis in GRACIA-1 study, 24 hours in the WEST trial, 3 to 12 hours in GRACIA-2, and 20 hours in the present study—is safer and reduces major bleeding complications.8,10,18 All these data seem to confirm that a routine but deferred invasive strategy may be more helpful in reducing infarct size and long-term mortality than an immediate approach.21

Importance of tissue-level perfusion The clinical implications of myocardial perfusion status after reperfusion in AMI have been widely investigated in several studies.13-16,22 The independent role of microvascular perfusion in predicting functional recovery, remodeling processes, and long-term prognosis has been largely demonstrated.13-16,22 Poor tissue-level perfusion results in poor LV function at follow-up. The CADILLAC study23 further confirms improved 1-year survival in patients who achieved greater tissue-level perfusion after therapy. Despite achieving TIMI flow grade 3 in N96% of infarct vessels, myocardial blush grade was normal only in 17% of patients and absent in about 50% of patients. In our study, successful IRA stenting was obtained in about 90% of patients allocated to invasive strategy, whereas normal tissue perfusion was achieved in 28% of patients in group A, 34% in group B, and only in 17% in group C. Interestingly, despite detection of at least 1 segment with contrast defect in most patients, the mean contrast defect extent after reperfusion was relatively small in patients allocated to invasive strategy (CDL 18% and 13%, CDA 13% and 12% of the entire left ventricle, groups A and B, respectively) with a slight further reduction at predischarge, whereas it was significantly higher in the lytic group (CDL 37%, CDA 39%). In accordance with previous studies, this observation may explain the significant LV function improvement detected at follow-up only in the first 2 groups. Noninvasive imaging by MCE may have several advantages over angiography in assessing coronary microcirculation. Myocardial blood flow is qualitatively assessed using myocardial blush grade, whereas a direct estimate of a nutrient flow may be obtained by MCE

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with a superior spatial resolution. The area with reduced or absent myocardial blush cannot be calculated; only an approximate estimate of tissue-level perfusion in the IRA territory may be obtained by coronary angiography. Conversely, the perfusion defect extent may be easily calculated by MCE. In particular, parametric analysis automatically quantifies dynamic perfusion information, and the perfusion defect area may be calculated in few seconds.

Study limitations Patients presenting N3 hours after symptom onset, in cardiogenic shock, with previous myocardial infarction, and with inhospital unstable clinical conditions were excluded from this study; elderly patients (N80 years) were also excluded to reduce the risk of bleeding complications, thus an intent-to-treat analysis could not be performed. In this pilot study, power calculation was not performed, and the sample size was based on our previous MCE studies12–17; thus, because the number of patients enrolled is relatively small, results of the present study cannot necessarily be transferred to the treatment of patients with STEMI in general practice. Future large longitudinal studies are needed. However, this study was not powered to find the best reperfusion strategy in patients with STEMI but was devoted to find an explanation for the positive results obtained combining early PCI after timely pharmacologic reperfusion.3–10 Patients treated by TNK only did not receive abciximab as the other 2 groups. Because abciximab is known to improve microvascular perfusion, part of the beneficial effect attributed to PCI may be due to abciximab instead. However, as shown in the CADILLAC study,24 clinical benefits of primary stenting are independent of abciximab use. In the recent GRACIA-2 trial,18 similar results were obtained by using primary or facilitated PCI, although abciximab was not used in the facilitated arm. Clinical implications Our data suggest the concept that timely and successful lysis does not improve microvascular perfusion compared with primary PCI alone. Even after very early thrombolysis, a delayed aggressive management within 24 hours after admission is necessary to better preserve microvascular perfusion. This combined strategy does not result in any additional improvement in microvascular perfusion beyond what is achieved by primary PCI but may be a useful alternative strategy in the breal worldQ of acute coronary syndromes in large cities where the time to balloon inflation is usually longer than recommended. There is still a high proportion of patients for whom primary PCI is not available who could benefit if they first receive treatment with thrombolytics.

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