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Distal protection device protects microvascular integrity during primary percutaneous intervention in acute myocardial infarction: A prospective, randomized, multicenter trial
International Journal of Cardiology 123 (2008) 162 – 168 www.elsevier.com/locate/ijcard
Distal protection device protects microvascular integrity during primary percutaneous intervention in acute myocardial infarction: A prospective, randomized, multicenter trial☆ Seung-Jea Tahk a,⁎, Byoung-Joo Choi a , So-Yeon Choi a , Myeong-Ho Yoon a , Hyeon-Cheol Gwon b , Geu-Ru Hong c , Young-Jo Kim c , Seung-Ho Hur d , Kwon-Bae Kim d , Bon-Kwon Koo e , Seung-Hwan Lee f , Junghan Yoon f a
Department of Cardiology, Ajou University School of Medicine, San 5 Wonchun-dong, Yeongtong-gu, Suwon, 443-721, Republic of Korea b Sungkyunkwan University Samsung Medical Center, Republic of Korea c Yeungnam University Hospital, Republic of Korea d Keimyong University Dongsan Medical Center, Republic of Korea e Seoul National University, Republic of Korea f Yonsei University Wonju College of Medicine Christian Hospital, Republic of Korea Received 23 August 2006; received in revised form 8 March 2007; accepted 30 March 2007 Available online 8 May 2007
Abstract Background: Distal protection during primary angioplasty in acute myocardial infarction (AMI) is the subject of recent controversy. The present study was designed to determine whether the distal embolic protection preserves myocardial microvascular integrity and improves clinical outcomes in patients with AMI. Methods: A total of 116 AMI patients presenting within 12 h of onset of symptoms were enrolled at 7 angioplasty centers. They were randomly assigned to either primary angioplasty with distal protection group (DP; n = 60) or angioplasty alone group (Controls; n = 56). Results: After primary angioplasty, achievement of final Thrombolysis In Myocardial Infarction (TIMI) grade 3 and TIMI Myocardial Perfusion (TMP) grade 3 were more frequent in the DP group than in the control group [58/60 (96%) vs. 43/56 (81%), p = 0.016; and 39/60 (65%) vs. 20/56 (38%), p = 0.001, respectively]. After primary angioplasty, the baseline and hyperemic averaged peak velocities were significantly higher (23.2 ± 11.5 vs. 18.0 ± 6.9 cm/s, p = 0.029; and 39.2 ± 16.7 vs. 30.6 ± 10.8 cm/s, p = 0.014, respectively) and the baseline and hyperemic microvascular resistance indices were significantly lower (4.18 ± 2.22 vs. 5.34 ± 2.25 mm Hg cm− 1 s, p = 0.036; and 2.38 ± 1.39 vs. 3.11 ± 1.32 mm Hg cm− 1 s, p = 0.030, respectively) in the DP group. Patients in the DP group showed more favorable phasic coronary flow pattern in diastolic deceleration time (679 ± 262 vs. 519 ± 289 ms, p = 0.035; and 751 ± 246 vs. 616 ± 269 ms, p = 0.035, respectively). Major adverse cardiac events at 6 months occurred with similar frequency in both groups (8.7% vs. 11.1%, p = 0.400). Conclusions: Distal protection device effectively preserves microvascular integrity during primary angioplasty in AMI. Distal protection, however, did not improve clinical outcomes. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Myocardial infarction; Angioplasty; Embolization
1. Background
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This study was supported in part by Medtronic, Inc. ⁎ Corresponding author. Tel.: +82 31 219 5712; fax: +82 31 219 5708. E-mail address: [email protected] (S.-J. Tahk).
0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.03.124
Cardiac mortality from acute myocardial infarction (AMI) has remarkably decreased since the introduction of primary angioplasty. It is now obvious that mechanical reperfusion with primary angioplasty, when feasible, is superior to
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systemic thrombolytic therapy in improving angiographic and clinical outcomes in patients with myocardial infarction with ST-segment elevation [1,2]. However, deterioration of coronary flow after removing of epicardial stenosis has been also reported in many patients of AMI [3,4]. It has been suggested that this flow deterioration is primarily caused by microembolism during the revascularization procedure [5–7]. Distal embolization is relatively frequent among patients undergoing primary angioplasty for AMI [8]. The presence of a large thrombus burden at the lesion site and atheromatous materials released by plaque rupture during revascularization procedure such as balloon inflation or stent deployment, lead to distal embolization which results in further damage to myocardial microcirculation, and impedes optimal salvage of infarcted myocardium [9]. Several recent studies have suggested that mechanical distal protection during primary angioplasty in patients with AMI may improve angiographic and clinical outcomes [10– 12]. But distal embolization and prevention of it during revascularization procedure is nevertheless the subject of recent controversy. The present study was designed to determine whether the distal embolic protection effectively preserves microvascular integrity of myocardium and improves clinical outcomes in patients with AMI.
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potentially limit the anticipated survival to less than 1 year. Patients were randomized in the order in which they were enrolled. Written informed consent was obtained prior to randomization. 2.2. Study protocol All patients received aspirin (300 mg) and clopidogrel (300– 600 mg) prior to intervention, based on the results of recent studies [13,14] which have indeed found that 6 h or longer are needed with a 300-mg loading dose of clopidogrel, or larger doses in the range of 600 mg are necessary to achieve maximal effects more rapidly. Activated clotting time of 300 s was maintained during PCI with intravenous unfractionated heparin. Stenting of the identified lesion was attempted in all patients and if necessary, high pressure ballooning followed the stenting procedure. Angioplasty in non-infarct-related artery and glycoprotein IIb/IIIa platelet receptor inhibitor were permitted. But usage of glycoprotein IIb/IIIa platelet receptor inhibitor was strongly discouraged. In the DP group, PercuSurge GuardWire system (Medtronic Inc; Santa Rosa, CA) was used for distal protection. Thrombolysis in Myocardial Infarction (TIMI) and
2. Materials and methods The present study was a prospective, randomized, multicenter trial to evaluate the efficacy of distal protection device during primary angioplasty of ST-segment elevated myocardial infarction (STEMI) patients. The coordinating laboratory was at the Cardiovascular Center in Ajou University Hospital, Suwon, Korea. Seven angioplasty centers in Korea participated in this study. Fig. 1 shows a brief outline of the study. 2.1. Study population First-time STEMI patients who underwent primary percutaneous coronary intervention (PCI) within 12 h after symptom onset were enrolled. The clinical inclusion criteria were first onset persistent chest pain more than 30 min with more than 2 mV ST-segment elevations in at least two contiguous leads. Patients were randomly assigned to either primary angioplasty with distal protection group (DP) or primary angioplasty alone group (control) if the reference vessel diameter of target lesion was 2.75–4.5 mm, diameter stenosis more than 70%, and if the lesion length was short enough to be covered with a single stent deployment. Exclusion criteria included the following: left ventricular ejection fraction ≤ 25%; left main disease; cardiogenic shock; bifurcation lesions, saphenous vein graft or arterial graft lesions; history of bleeding tendency or coagulopathy; pregnancy; allergy to radiocontrast dye, aspirin, clopidogrel or heparin; and any comorbid conditions that could
Fig. 1. Study design. STEMI = ST-segment elevated myocardial infarction; DP = distal protection; TIMI = thrombolysis in myocardial infarction; TMP = TIMI myocardial perfusion; MACE = major adverse cardiac event.
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TIMI Myocardial Perfusion (TMP) grades were assessed before and after intervention via a final angiography that was obtained during more than 10 cardiac cycles in the adequate view angles. TIMI [15] and TMP [16] grades were defined as previously described. Baseline echocardiography was performed before or just after the procedure. The ethics board of each site approved the protocol prior to the enrollment of patients. 2.3. Distal protection procedure The GuardWire temporary occlusion balloon was positioned several centimeters beyond the stenosis. If it was difficult for the GuardWire temporary occlusion balloon to cross the lesion, low pressure (less than 4 atm) predilation using standard floppy guidewire and 1.5–2.0 mm balloon was permitted before the insertion of GuardWire. Aspiration procedure using an Export catheter was performed after deployment of a stent (after high pressure inflation) but not before and after balloon predilation. The operators were instructed to perform the procedure as simply as possible and no additional procedure was permitted after the deflation of GuardWire temporary occlusion balloon. If it was necessary to perform an additional procedure, the operators were instructed to reinflate the GuardWire temporary balloon. 2.4. Measurement of coronary flow and phasic coronary flow velocity pattern To assess the microvascular integrity and viability of salvaged myocardium immediate after PCI, coronary flow and phasic coronary velocity patterns were measured and analyzed. Coronary flow was measured using 0.014 in. Doppler wire (FloWire; Cardiometrics; Mountain View, CA), just distal to the deployed stent after successful PCI. Maximal hyperemia was induced by intracoronary bolus administration of adenosine (24 μg for the right coronary artery, 36–48 μg for the left coronary artery). The coronary flow velocity reserve (CFR) was defined as the ratio of the hyperemic averaged peak velocity (APV) to the baseline APV. The microvascular resistance index (MVRI) was calculated from the mean aortic blood pressure divided by APV at baseline, and during hyperemia respectively. Deceleration times of the diastolic flow velocity (DDT) were measured and averaged for their mean values during three consecutive cardiac cycles at baseline and during hyperemia.
The primary end point of this study was to assess the benefit of distal protection device for salvaging myocardium immediate after PCI. TIMI, TMP grade, coronary flow and phasic coronary flow velocity pattern were measured after PCI to help measure and analyze such potential benefit. The secondary end point was the evaluation of clinical improvement in patients where a distal protection device was used in primary angioplasty of acute myocardial infarction. This was analyzed by documenting death, reinfarction and ischemia-driven target vessel revascularization (TVR) at 6 months after PCI. Reinfarction was defined by the presence of recurrent ischemic symptoms or electrocardiographic changes accompanied by a creatine kinase (CK) level that was more than twice the upper limit of the normal range (with an elevated MB isoform level) or more than 50% higher than the previous value obtained during hospitalization. Revascularization of the target vessel was considered to have been prompted by ischemia if there was evidence of ischemia during functional testing or of angina. 2.7. Statistical analysis According to the previous study [17], we assumed a baseline APV of 16.3 ± 8.6 cm/s in the control group. We designed our study to have a power of 80% (β = 0.2) to detect an improvement in maximal APV by 30% with a level of significance of 0.05 (α error = 0.05). These assumptions yielded a sample size of 49 patients in each treatment arm. For change in TMP grade, a sample size of approximately 47 patients was required for 80% power and a level of significance of 0.05 to detect an expected change of 30%, assuming a rate of TMP grade 3 of 30% in the control group [18]. To account for potential dropouts, we intended to include 60 patients in each treatment arm. Data are expressed as percentages for discrete variables and as the mean ± standard deviation for continuous variables. The continuous variables of the clinical, angiographic and intracoronary Doppler flow data were compared by the means between the two groups using Student-t test. The categorical variables of the clinical characteristics, angiographic TIMI and TMP grades, were compared by χ2 analysis or the Fisher exact test. Statistical significance was set at p b 0.05. 3. Results 3.1. Clinical characteristics
2.5. Definition of device success Device success was defined as technically successful deployment of GuardWire system, complete occlusion of antegrade flow, and successful aspiration through an Export catheter. 2.6. Follow-up and study endpoints Clinical and echocardiographic follow-up was performed at 1 and 6 months after the procedure in an outpatient clinic.
From December 12, 2003 to October 29, 2004, 118 acute myocardial infarct patients underwent randomization in seven angioplasty centers prior to primary angioplasty. Of the initially randomized patients, two cases were excluded from further analysis: one had cardiogenic shock and the other received stenting of left main coronary artery due to dissection. Thus, a total of 116 patients (mean age 57.3 ± 14.3, 91 males, 25 females) were eventually enrolled. Sixty patients (51.7%) were randomly assigned to receive angioplasty with distal protection and the other fifty six patients (48.3%) were
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randomly assigned to the control group. The Two study groups were well matched with respect to baseline clinical and angiographic characteristics (Table 1).
Table 2 Procedural characteristics and post-PCI angiographic results
3.2. Procedural and angiographic results
Post-PCI Reference vessel size (mm) MLD (mm) DS (%) GP IIb/IIIa inhibitors Stent implantation at the target lesion (%) Implanted stents per patient (n) Direct stenting (%) Post-dilation (%) Reinflation of distal occlusion balloon (%) Time from hospital arrival to stent implantation (min) Post-PCI TIMI flow grade TIMI 0/1 TIMI 2 TIMI 3 Post-PCI TMP grade TMP 0/1 TMP 2 TMP 3
In the DP group, site-reported device success rate was 96.7% (58/60). All patients undergoing successful distal protection procedure received complete protection with PercuSurge occlusion balloon during the revascularization procedure including predilation, stent deployment and high pressure ballooning. And no procedure related complication was documented in the DP group. There was only one patient who was administered glycoprotein IIb/IIIa platelet receptor inhibitor during procedure. Table 2 provides the post-PCI angiographic results. All the target lesions were successfully deployed with a stent in both
Table 1 Baseline clinical and angiographic characteristics
Age (years) Male gender Anterior infarction Risk factor Hypertension Diabetes mellitus Smoking Lipid profile (mg/dl) Total cholesterol Triglyceride HDL-cholesterol LDL-cholesterol Left ventricular EF (%) LVWMSI Time from symptom onset to stenting (min) CAD extension One-vessel disease Two-vessel disease Three-vessel disease Infarct-related artery Left anterior descending Left circumflex Right coronary Before PCI Reference vessel size(mm) MLD (mm) DS (%) Baseline TIMI flow grade TIMI 0/1 TIMI 2 TIMI 3
DP group (n = 60)
Control group (n = 56)
p value
55.9 ± 13.9 51 (85%) 32 (53%)
58.8 ± 14.5 40 (71%) 31 (56%)
0.265 0.113 0.782
21 (36%) 12 (20%) 40 (68%)
30 (54%) 12 (21%) 32 (57%)
0.086 1.000 0.254
181.7 ± 33.2 131.4 ± 92.9 42.6 ± 11.4 113.5 ± 34.5 52.1 ± 9.4 1.44 ± 0.30 339.3 ± 189.2
191.6 ± 40.9 128.9 ± 89.3 41.9 ± 9.6 123.0 ± 36.8 49.0 ± 11.2 1.53 ± 0.37 327.8 ± 209.5
0.165 0.886 0.746 0.170 0.104 0.135 0.772 0.086
38 (63%) 14 (23%) 8 (13%)
44 (80%) 9 (16%) 2 (4%)
32 (53%)
31(56%)
4 (7%) 24 (40%)
5 (9%) 19 (35%)
3.4 ± 0.4 0.17 ± 0.27 95.5 ± 7.4
3.3 ± 0.5 0.18 ± 0.38 94.7 ± 11.1
40 (67%) 11 (18%) 9 (15%)
41 (76%) 6 (11%) 7 (13%)
0.782
0.163 0.854 0.642 0.466
DP = distal protection; HDL = high density lipoprotein; LDL = low density lipoprotein; EF = ejection fraction; LVWMSI = left ventricular wall motion score index; CAD = coronary artery disease; PCI = percutaneous coronary intervention; MLD = minimal lumen diameter; DS = diameter stenosis; TIMI = thrombolysis in myocardial infarction.
DP group (n = 60)
Control group (n = 56)
p value
3.4 ± 0.4 3.1 ± 0.4 10.0 ± 7.6 0 100 (60/60)
3.3 ± 0.5 3.0 ± 0.5 10.5 ± 8.3 1 100 (56/56)
0.163 0.332 0.747 – 1.000
1.22 0 (0/60) 26.7% (16/60) 5.0% (3/60)
1.16 1.8 (1/56) 23.2% (13/56) –
0.875 0.761 0.458
107.8 ± 25.4
94.5 ± 18.9
0.156
1 (2%) 1 (2%) 58 (96%)
1 (2%) 9 (17%) 43 (81%)
3 (5%) 18 (30%) 39 (65%)
17 (32%) 16 (30%) 20 (38%)
0.016
0.001
PCI = percutaneous coronary intervention; DP = distal protection; MLD = minimal lumen diameter; DS = diameter stenosis; GP = glycoprotein; TIMI = thrombolysis in myocardial infarction; TMP = TIMI myocardial perfusion.
groups. Peak cardiac enzyme after revascularization (CK-MB; 266.4 ± 180.2 μg/ml vs. 311.9 ± 174.0 μg/ml, p = 0.188) was similar in both groups. There were no significant differences between the two groups in the rates of implanted stents per patient (1.22 vs. 1.16, p = 0.875), direct stenting (0 (0%) vs. 1 (1.8%), p = 0.761), post-dilation (16 (26.7%) vs. 13 (23.2%), Table 3 Coronary flow parameters and phasic coronary flow patterns
Heart rate (pulse/min) Baseline mean blood pressure (mm Hg) Hyperemic mean blood pressure (mm Hg) Flow velocity parameters bAPV (cm/s) hAPV (cm/s) CFR bMVRI (mm Hg cm− 1 s) hMVRI (mm Hg cm− 1 s) Coronary phasic flow patterns bDDT (ms) hDDT (ms)
DP group (n = 35)
Control group (n = 33)
p value
77.7 ± 16.1 76.6 ± 11.8
78.2 ± 16.5 84.2 ± 18.1
0.670 0.043
74.9 ± 12.5
84.0 ± 17.7
0.017
23.2 ± 11.5 39.2 ± 16.7 1.80 ± 0.64 4.18 ± 2.22 2.38 ± 1.39
18.0 ± 6.9 30.6 ± 10.8 1.80 ± 0.60 5.34 ± 2.25 3.11 ± 1.32
0.029 0.014 0.979 0.036 0.030
669 ± 262 751 ± 246
519 ± 282 616 ± 269
0.026 0.035
DP = distal protection; bAPV = baseline averaged peak velocity; hAPV = hyperemic averaged peak velocity; CFR = coronary flow reserve; bMVRI = baseline microvascular resistance index; hMVRI = hyperemic microvascular resistance index; bDDT = baseline diastolic deceleration time; hDDT = hyperemic diastolic deceleration time.
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Table 4 Clinical outcome and left ventricular function at six months
Composite MACE at 30 days Death TVR Reinfarction Composite MACE at 6 months Death TVR Reinfarction
control group (679± 262 vs. 519 ± 289 ms, p= 0.035; and 751 ± 246 vs. 616 ± 269 ms, p= 0.035, respectively) (Table 3).
DP group (n = 54/60)
Control group (n = 52/56)
p value
2
2
0.757
– 1 1 4
2 0 0 5
– 3 1
2 2 1
0.400
Left ventricular function at DP group 6 months (n = 48/60)
Control group (n = 47/56)
p value
Ejection fraction (%) LVWMSI ΔEjection fraction (%) ΔLVWMSI
54.6 ± 10.3 1.40 ± 0.32 5.65 ± 8.64 −0.09 ± 0.26
0.239 0.118 0.832 0.498
58.1 ± 11.4 1.28 ± 0.27 6.18 ± 9.46 − 0.13 ± 0.23
DP = distal protection; MACE = major adverse cardiac event; TVR = target vessel revascularization; LVWMSI = left ventricular wall motion score index; ΔEjection fraction = difference between 6 months follow-up ejection fraction and baseline ejection fraction; ΔLVWMSI = difference between 6 months follow-up LVWMSI and baseline LVWMSI.
p = 0.458) and time from hospital arrival to stent implantation (339.3 ± 189.2 min vs. 327.8 ± 209.5 min, p = 0.772). In the DP group, 3 cases of the temporary occlusion balloon reinflation for further revascularization procedures were performed, two of which were for high-pressure ballooning and the other one for provisional ballooning of a big side branch. After primary PCI, achievement of final TIMI grade 3 was more frequent in the DP group than in the control group (58 (96%) vs. 43 (81%), p = 0.016). The proportion of patients with TMP grade 3 after revascularization was significantly higher in the DP group than in the control group (39 (65%) vs. 20 (38%), p = 0.001). The proportion of TMP grade 3 remained higher in the DP group than in the control group when TMP grades were analyzed among the patients subgroup achieving TIMI grade 3 (39 (67%) vs. 20 (47%), p = 0.007). 3.3. Coronary flow velocity parameters and phasic coronary flow velocity patterns There were no significant differences in heart rate and baseline mean aortic blood pressure between the two groups. After primary PCI, the baseline APV and hyperemic APV were significantly higher in the DP group than in the control group (23.2± 11.5 vs. 18.0 ± 6.9 cm/s, p = 0.029; and 39.2± 16.7 vs. 30.6± 10.8 cm/s, p= 0.014, respectively). Baseline and hyperemic MVRI were significantly lower in the DP group than in the control group (4.18 ± 2.22 vs. 5.34 ± 2.25 mm Hg cm− 1 s, p = 0.036; and 2.38 ± 1.39 vs. 3.11 ± 1.32 mm Hg cm− 1 s, p = 0.030, respectively). However, the two groups did not have any significant differences in CFR. The baseline and hyperemic DDT were significantly longer in the DP group than in the
3.4. Late clinical events: Six-month clinical outcome and left ventricular function Table 4 summarizes 1 and 6 months clinical outcomes and left ventricular function changes. At six months secondary end points were reached in 90.0% of the DP group and 92.9% of the control group. The rates of MACE at 6 months were 7.4% and 9.3% in each group. There were no significant differences in composite endpoints of death, TVR and reinfarction between the two groups (p = 0.40) at both 30 days and 6 months. Improvement of left ventricular function (ΔEjection fraction between baseline and 6 months; 6.18± 9.46% vs. 5.65± 8.64%, p = 0.832) and regional wall motion abnormalities (ΔLeft ventricular wall motion score index between baseline and 6 months; −0.13 ± 0.23 vs. −0.09± 0.26, p = 0.498) were similar in both groups. Randomized treatment modalities also did not affect the left ventricular function improvement. 4. Discussion The mechanism of suboptimal myocardial salvage after primary angioplasty of acute myocardial infarction is multifactorial and has not yet been fully elucidated. Prolonged cessation of coronary blood flow leads to permanent ischemic damage of myocardial microstructure. Subsequent restoration of normal blood flow to the myocardium produces the so-called “reperfusion injury” by a variety of mechanisms [19–21]. Finally, the atheroembolism during the revascularization procedure may add to the extent of myocardial damage [9]. To optimize the salvage of infarct myocardium with revascularization, many trials have aimed at reducing the atheroembolic injury using a variety of innovative devices to filter these microemboli [10–12]. The present study was also designed with this concept in mind. The present study demonstrates the preservation of distal microcirculation during primary PCI using a distal protection device in STEMI patients. TMP grade measured immediately after PCI showed a significantly higher incidence of TMP grade 3 in the DP group. Even among the subgroup of patients achieving TIMI flow grade 3, the distal protection device successfully protected microvasculature from microembolism during the primary PCI. Patients in the DP group had higher APV and lower MVRI after elimination of epicardial coronary occlusion. This observation again underlines the fact that the distal protection device protects the microvascular structure of infarct myocardium from further damage. Intravascular plugging of necrotic cell debris, thrombotic and atheromatous material combined with ischemic injury interfere with coronary blood flow and decrease the coronary flow velocity and increase microvascular resistance [22]. Therefore higher APV and lower MVRI in the patients of the DP group imply that their microvascular integrities are preserved well from microembolism during
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primary PCI. Consistent results were demonstrated by REMEDIA (Randomized evaluation of the effect of mechanical reduction of distal embolization by thrombus aspiration in primary and rescue angioplasty) study using contrast echocardiogram. In the study, the patients treated with a thrombus aspiration filter device revealed significantly lower contrast score index and contrast defect, which suggests the beneficial effects of distal embolization reduction [23]. Furthermore, in extensively damaged myocardium of AMI, the available intravascular space is considerably decreased and the microvascular resistance is elevated such that coronary blood flow rapidly fills the intact intramyocardial blood pool during the diastolic phase with a rapid subsequent reduction [22]. This results in a rapidly decelerating diastolic flow and an early systolic retrograde flow or a decreased systolic flow. Kawamoto et al. [24] and Akasaka et al. [25] advocated that SAPV less than 6.5 cm/s, or early systolic flow reversal and DDT less than 600 ms immediate after PCI indicates a low probability of improvement in the left ventricular function. Thus, the significantly longer DDT in the DP group (versus the control group) suggests a favorable pattern of reduction in myocardial injury. EMERALD [26] (Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris) study, however, showed that the distal embolic protection in primary PCI of AMI did not preserve microvascular integrity immediate after PCI, which were different results from our study. Some likely explanations are as follows. First, the patients randomized to receive distal protection in EMERALD study received complete distal protection during PCI only in 79% of patients, because 21% of these patients underwent some additional procedures after the retrieval of distal occlusion balloon or received incomplete protection during PCI. Secondly, a large proportion of glycoprotein IIb/IIIa platelet receptor inhibitor usage in EMERALD study may have possibly diminished the superiority of distal protection devices over PCI only. Because platelet and fibrin plugging is an important contributor to the pathogenesis of distal microembolization [6,27,28], administration of glycoprotein IIb/IIIa platelet receptor inhibitor in PCI only group may reduce the potential benefit of the distal protection device. Thirdly, EMERALD study patients had less jeopardized myocardium compared to those in the present study. The length of time from onset of symptoms to reperfusion in EMERALD study was shorter (233 min in distal the protection group, 211 min in the control group, p = 0.02) than that of the present study. The time interval to reperfusion is an important factor in rescuing ischemic myocardium in AMI [29]. Low risk myocardium may diminish these differences. Our study, however, also did not demonstrate the improvement of clinical outcome in the DP group that is compatible with the results of EMERALD study. While the distal protection device preserved the microvascular integrity immediate after PCI, that preservation may not be sufficient to be linked to the improvement in left ventricular function.
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Considering the study results in PCI of degenerated saphenous vein grafts [30,31], these might be due to incomplete protection of side branches (e.g., diagonal and obtuse marginal branches). This can be potentially overcome by proximal occlusion system [32]. Paradoxically, the additional time required for distal protection procedure might increase the infarct size. PercuSurge distal occlusion balloon system occludes the distal blood flow completely during the procedure which may cause unintentional damage to the myocardium. Finally another mechanism besides distal microembolization such as reperfusion injury, local inflammatory cytokines and endothelial dysfunction etc. should be considered in conjunction with distal protection for improving clinical outcomes. 4.1. Study limitations Though our study was designed as prospective, the small number of patients is a major limiting factor. The sample size was calculated on assumptions related to any improvement of microvascular integrities, instead of the secondary end point of the trial. This allowed us to enroll fewer patients at the cost of a reduced power with regard to the secondary end point. Small sample size might be underpowered to demonstrate the efficacy of distal protection in clinical outcome improvement. 5. Conclusion Adjunctive therapy with distal protection device in primary PCI of STEMI patients preserves microvascular integrity when compared to isolated PCI. It appears that preservation of microvascular integrity by distal protection device may not be sufficient to result in an improvement in clinical outcomes. References [1] Zahn R, Schiele R, Schneider S, et al. Primary angioplasty versus intravenous thrombolysis in acute myocardial infarction: can we define subgroups of patients benefiting most from primary angioplasty? Results from the pooled data of the Maximal Individual Therapy in Acute Myocardial Infarction Registry and the Myocardial Infarction Registry. J Am Coll Cardiol 2001;37:1827–35. [2] Andersen HR, Nielsen TT, Rasmussen K, et al. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 2003;349:733–42. [3] Iwakura K, Ito H, Nishikawa N, et al. Early temporal changes in coronary flow velocity patterns in patients with acute myocardial infarction demonstrating the “no-reflow” phenomenon. Am J Cardiol 1999;84:415–9. [4] Piana RN, Paik GY, Moscucci M, et al. Incidence and treatment of ‘noreflow’ after percutaneous coronary intervention. Circulation 1994;89:2514–8. [5] Kotani J, Nanto S, Mintz GS, et al. Plaque gruel of atheromatous coronary lesion may contribute to the no-reflow phenomenon in patients with acute coronary syndrome. Circulation 2002;106:1672–7. [6] Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease. Circulation 2000;101:570–80.
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[21] Engler RL, Dahlgren MD, Morris DD, et al. Role of leukocytes in response to acute myocardial ischemia and reflow in dogs. Am J Physiol 1986;251:H314–23. [22] Ito H, Iwakura K. Assessing the relation between coronary reflow and myocardial reflow. Am J Cardiol 1998;81:8G–12G. [23] Galiuto L, Garramone B, Burzotta F, et al, REMEDIA investigators. Thrombus aspiration reduces microvascular obstruction after primary coronary intervention: a myocardial contrast echocardiography substudy of the REMEDIA Trial. J Am Coll Cardiol 2006;48:1355–60. [24] Kawamoto T, Yoshida K, Akasaka T, et al. Can coronary flow velocity pattern after percutaneous transluminal coronary angioplasty (correlation of angiography) predict recovery of regional left ventricular function in patients with acute myocardial infarction? Circulation 1999;27:339–45. [25] Akasaka T, Yoshida K, Kawamoto T, et al. Relation of phasic coronary flow velocity characteristics with TIMI perfusion grade and myocardial recovery after primary percutaneous transluminal coronary angioplasty and rescue stenting. Circulation 2000;101:2361–7. [26] Stone GW, Webb J, Cox DA, et al, Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris (EMERALD) Investigators. Distal microcirculatory protection during percutaneous coronary intervention in acute ST-segment elevation myocardial infarction: a randomized controlled trial. JAMA 2005;293:1063–72. [27] Seydoux C, Goy JJ, Davies G. Platelet and neutrophil imaging techniques in the investigation of the response to thrombolytic therapy and the no-reflow phenomenon. Am Heart J 1993;125:1142–7. [28] Michaels AD, Gibson CM, Barron HV. Microvascular dysfunction in acute myocardial infarction: focus on the roles of platelet and inflammatory mediators in the no-reflow phenomenon. Am J Cardiol 2000;85:50B–60B. [29] Rezkalla SH, Kloner RA. No-reflow phenomenon. Circulation 2002;105:656–62. [30] Carlino M, De Gregorio J, Di Mario C, et al. Prevention of distal embolization during saphenous vein graft lesion angioplasty. Experience with a new temporary occlusion and aspiration system. Circulation 1999;99:3221–3. [31] Grube E, Schofer JJ, Webb J, et al, Saphenous Vein Graft Angioplasty Free of Emboli (SAFE) Trial Study Group. Evaluation of a balloon occlusion and aspiration system for protection from distal embolization during stenting in saphenous vein grafts. Am J Cardiol 2002;89:941–5. [32] Sievert H, Wahr DW, Schuler G, et al. Effectiveness and safety of the Proxis system in demonstrating retrograde coronary blood flow during proximal occlusion and in capturing embolic material. Am J Cardiol 2004;94:1134–9.
Distal protection device protects microvascular integrity during primary percutaneous intervention in acute myocardial infarction: A prospective, randomized, multicenter trial☆ Seung-Jea Tahk a,⁎, Byoung-Joo Choi a , So-Yeon Choi a , Myeong-Ho Yoon a , Hyeon-Cheol Gwon b , Geu-Ru Hong c , Young-Jo Kim c , Seung-Ho Hur d , Kwon-Bae Kim d , Bon-Kwon Koo e , Seung-Hwan Lee f , Junghan Yoon f a
Department of Cardiology, Ajou University School of Medicine, San 5 Wonchun-dong, Yeongtong-gu, Suwon, 443-721, Republic of Korea b Sungkyunkwan University Samsung Medical Center, Republic of Korea c Yeungnam University Hospital, Republic of Korea d Keimyong University Dongsan Medical Center, Republic of Korea e Seoul National University, Republic of Korea f Yonsei University Wonju College of Medicine Christian Hospital, Republic of Korea Received 23 August 2006; received in revised form 8 March 2007; accepted 30 March 2007 Available online 8 May 2007
Abstract Background: Distal protection during primary angioplasty in acute myocardial infarction (AMI) is the subject of recent controversy. The present study was designed to determine whether the distal embolic protection preserves myocardial microvascular integrity and improves clinical outcomes in patients with AMI. Methods: A total of 116 AMI patients presenting within 12 h of onset of symptoms were enrolled at 7 angioplasty centers. They were randomly assigned to either primary angioplasty with distal protection group (DP; n = 60) or angioplasty alone group (Controls; n = 56). Results: After primary angioplasty, achievement of final Thrombolysis In Myocardial Infarction (TIMI) grade 3 and TIMI Myocardial Perfusion (TMP) grade 3 were more frequent in the DP group than in the control group [58/60 (96%) vs. 43/56 (81%), p = 0.016; and 39/60 (65%) vs. 20/56 (38%), p = 0.001, respectively]. After primary angioplasty, the baseline and hyperemic averaged peak velocities were significantly higher (23.2 ± 11.5 vs. 18.0 ± 6.9 cm/s, p = 0.029; and 39.2 ± 16.7 vs. 30.6 ± 10.8 cm/s, p = 0.014, respectively) and the baseline and hyperemic microvascular resistance indices were significantly lower (4.18 ± 2.22 vs. 5.34 ± 2.25 mm Hg cm− 1 s, p = 0.036; and 2.38 ± 1.39 vs. 3.11 ± 1.32 mm Hg cm− 1 s, p = 0.030, respectively) in the DP group. Patients in the DP group showed more favorable phasic coronary flow pattern in diastolic deceleration time (679 ± 262 vs. 519 ± 289 ms, p = 0.035; and 751 ± 246 vs. 616 ± 269 ms, p = 0.035, respectively). Major adverse cardiac events at 6 months occurred with similar frequency in both groups (8.7% vs. 11.1%, p = 0.400). Conclusions: Distal protection device effectively preserves microvascular integrity during primary angioplasty in AMI. Distal protection, however, did not improve clinical outcomes. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Myocardial infarction; Angioplasty; Embolization
1. Background
☆
This study was supported in part by Medtronic, Inc. ⁎ Corresponding author. Tel.: +82 31 219 5712; fax: +82 31 219 5708. E-mail address: [email protected] (S.-J. Tahk).
0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.03.124
Cardiac mortality from acute myocardial infarction (AMI) has remarkably decreased since the introduction of primary angioplasty. It is now obvious that mechanical reperfusion with primary angioplasty, when feasible, is superior to
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systemic thrombolytic therapy in improving angiographic and clinical outcomes in patients with myocardial infarction with ST-segment elevation [1,2]. However, deterioration of coronary flow after removing of epicardial stenosis has been also reported in many patients of AMI [3,4]. It has been suggested that this flow deterioration is primarily caused by microembolism during the revascularization procedure [5–7]. Distal embolization is relatively frequent among patients undergoing primary angioplasty for AMI [8]. The presence of a large thrombus burden at the lesion site and atheromatous materials released by plaque rupture during revascularization procedure such as balloon inflation or stent deployment, lead to distal embolization which results in further damage to myocardial microcirculation, and impedes optimal salvage of infarcted myocardium [9]. Several recent studies have suggested that mechanical distal protection during primary angioplasty in patients with AMI may improve angiographic and clinical outcomes [10– 12]. But distal embolization and prevention of it during revascularization procedure is nevertheless the subject of recent controversy. The present study was designed to determine whether the distal embolic protection effectively preserves microvascular integrity of myocardium and improves clinical outcomes in patients with AMI.
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potentially limit the anticipated survival to less than 1 year. Patients were randomized in the order in which they were enrolled. Written informed consent was obtained prior to randomization. 2.2. Study protocol All patients received aspirin (300 mg) and clopidogrel (300– 600 mg) prior to intervention, based on the results of recent studies [13,14] which have indeed found that 6 h or longer are needed with a 300-mg loading dose of clopidogrel, or larger doses in the range of 600 mg are necessary to achieve maximal effects more rapidly. Activated clotting time of 300 s was maintained during PCI with intravenous unfractionated heparin. Stenting of the identified lesion was attempted in all patients and if necessary, high pressure ballooning followed the stenting procedure. Angioplasty in non-infarct-related artery and glycoprotein IIb/IIIa platelet receptor inhibitor were permitted. But usage of glycoprotein IIb/IIIa platelet receptor inhibitor was strongly discouraged. In the DP group, PercuSurge GuardWire system (Medtronic Inc; Santa Rosa, CA) was used for distal protection. Thrombolysis in Myocardial Infarction (TIMI) and
2. Materials and methods The present study was a prospective, randomized, multicenter trial to evaluate the efficacy of distal protection device during primary angioplasty of ST-segment elevated myocardial infarction (STEMI) patients. The coordinating laboratory was at the Cardiovascular Center in Ajou University Hospital, Suwon, Korea. Seven angioplasty centers in Korea participated in this study. Fig. 1 shows a brief outline of the study. 2.1. Study population First-time STEMI patients who underwent primary percutaneous coronary intervention (PCI) within 12 h after symptom onset were enrolled. The clinical inclusion criteria were first onset persistent chest pain more than 30 min with more than 2 mV ST-segment elevations in at least two contiguous leads. Patients were randomly assigned to either primary angioplasty with distal protection group (DP) or primary angioplasty alone group (control) if the reference vessel diameter of target lesion was 2.75–4.5 mm, diameter stenosis more than 70%, and if the lesion length was short enough to be covered with a single stent deployment. Exclusion criteria included the following: left ventricular ejection fraction ≤ 25%; left main disease; cardiogenic shock; bifurcation lesions, saphenous vein graft or arterial graft lesions; history of bleeding tendency or coagulopathy; pregnancy; allergy to radiocontrast dye, aspirin, clopidogrel or heparin; and any comorbid conditions that could
Fig. 1. Study design. STEMI = ST-segment elevated myocardial infarction; DP = distal protection; TIMI = thrombolysis in myocardial infarction; TMP = TIMI myocardial perfusion; MACE = major adverse cardiac event.
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TIMI Myocardial Perfusion (TMP) grades were assessed before and after intervention via a final angiography that was obtained during more than 10 cardiac cycles in the adequate view angles. TIMI [15] and TMP [16] grades were defined as previously described. Baseline echocardiography was performed before or just after the procedure. The ethics board of each site approved the protocol prior to the enrollment of patients. 2.3. Distal protection procedure The GuardWire temporary occlusion balloon was positioned several centimeters beyond the stenosis. If it was difficult for the GuardWire temporary occlusion balloon to cross the lesion, low pressure (less than 4 atm) predilation using standard floppy guidewire and 1.5–2.0 mm balloon was permitted before the insertion of GuardWire. Aspiration procedure using an Export catheter was performed after deployment of a stent (after high pressure inflation) but not before and after balloon predilation. The operators were instructed to perform the procedure as simply as possible and no additional procedure was permitted after the deflation of GuardWire temporary occlusion balloon. If it was necessary to perform an additional procedure, the operators were instructed to reinflate the GuardWire temporary balloon. 2.4. Measurement of coronary flow and phasic coronary flow velocity pattern To assess the microvascular integrity and viability of salvaged myocardium immediate after PCI, coronary flow and phasic coronary velocity patterns were measured and analyzed. Coronary flow was measured using 0.014 in. Doppler wire (FloWire; Cardiometrics; Mountain View, CA), just distal to the deployed stent after successful PCI. Maximal hyperemia was induced by intracoronary bolus administration of adenosine (24 μg for the right coronary artery, 36–48 μg for the left coronary artery). The coronary flow velocity reserve (CFR) was defined as the ratio of the hyperemic averaged peak velocity (APV) to the baseline APV. The microvascular resistance index (MVRI) was calculated from the mean aortic blood pressure divided by APV at baseline, and during hyperemia respectively. Deceleration times of the diastolic flow velocity (DDT) were measured and averaged for their mean values during three consecutive cardiac cycles at baseline and during hyperemia.
The primary end point of this study was to assess the benefit of distal protection device for salvaging myocardium immediate after PCI. TIMI, TMP grade, coronary flow and phasic coronary flow velocity pattern were measured after PCI to help measure and analyze such potential benefit. The secondary end point was the evaluation of clinical improvement in patients where a distal protection device was used in primary angioplasty of acute myocardial infarction. This was analyzed by documenting death, reinfarction and ischemia-driven target vessel revascularization (TVR) at 6 months after PCI. Reinfarction was defined by the presence of recurrent ischemic symptoms or electrocardiographic changes accompanied by a creatine kinase (CK) level that was more than twice the upper limit of the normal range (with an elevated MB isoform level) or more than 50% higher than the previous value obtained during hospitalization. Revascularization of the target vessel was considered to have been prompted by ischemia if there was evidence of ischemia during functional testing or of angina. 2.7. Statistical analysis According to the previous study [17], we assumed a baseline APV of 16.3 ± 8.6 cm/s in the control group. We designed our study to have a power of 80% (β = 0.2) to detect an improvement in maximal APV by 30% with a level of significance of 0.05 (α error = 0.05). These assumptions yielded a sample size of 49 patients in each treatment arm. For change in TMP grade, a sample size of approximately 47 patients was required for 80% power and a level of significance of 0.05 to detect an expected change of 30%, assuming a rate of TMP grade 3 of 30% in the control group [18]. To account for potential dropouts, we intended to include 60 patients in each treatment arm. Data are expressed as percentages for discrete variables and as the mean ± standard deviation for continuous variables. The continuous variables of the clinical, angiographic and intracoronary Doppler flow data were compared by the means between the two groups using Student-t test. The categorical variables of the clinical characteristics, angiographic TIMI and TMP grades, were compared by χ2 analysis or the Fisher exact test. Statistical significance was set at p b 0.05. 3. Results 3.1. Clinical characteristics
2.5. Definition of device success Device success was defined as technically successful deployment of GuardWire system, complete occlusion of antegrade flow, and successful aspiration through an Export catheter. 2.6. Follow-up and study endpoints Clinical and echocardiographic follow-up was performed at 1 and 6 months after the procedure in an outpatient clinic.
From December 12, 2003 to October 29, 2004, 118 acute myocardial infarct patients underwent randomization in seven angioplasty centers prior to primary angioplasty. Of the initially randomized patients, two cases were excluded from further analysis: one had cardiogenic shock and the other received stenting of left main coronary artery due to dissection. Thus, a total of 116 patients (mean age 57.3 ± 14.3, 91 males, 25 females) were eventually enrolled. Sixty patients (51.7%) were randomly assigned to receive angioplasty with distal protection and the other fifty six patients (48.3%) were
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randomly assigned to the control group. The Two study groups were well matched with respect to baseline clinical and angiographic characteristics (Table 1).
Table 2 Procedural characteristics and post-PCI angiographic results
3.2. Procedural and angiographic results
Post-PCI Reference vessel size (mm) MLD (mm) DS (%) GP IIb/IIIa inhibitors Stent implantation at the target lesion (%) Implanted stents per patient (n) Direct stenting (%) Post-dilation (%) Reinflation of distal occlusion balloon (%) Time from hospital arrival to stent implantation (min) Post-PCI TIMI flow grade TIMI 0/1 TIMI 2 TIMI 3 Post-PCI TMP grade TMP 0/1 TMP 2 TMP 3
In the DP group, site-reported device success rate was 96.7% (58/60). All patients undergoing successful distal protection procedure received complete protection with PercuSurge occlusion balloon during the revascularization procedure including predilation, stent deployment and high pressure ballooning. And no procedure related complication was documented in the DP group. There was only one patient who was administered glycoprotein IIb/IIIa platelet receptor inhibitor during procedure. Table 2 provides the post-PCI angiographic results. All the target lesions were successfully deployed with a stent in both
Table 1 Baseline clinical and angiographic characteristics
Age (years) Male gender Anterior infarction Risk factor Hypertension Diabetes mellitus Smoking Lipid profile (mg/dl) Total cholesterol Triglyceride HDL-cholesterol LDL-cholesterol Left ventricular EF (%) LVWMSI Time from symptom onset to stenting (min) CAD extension One-vessel disease Two-vessel disease Three-vessel disease Infarct-related artery Left anterior descending Left circumflex Right coronary Before PCI Reference vessel size(mm) MLD (mm) DS (%) Baseline TIMI flow grade TIMI 0/1 TIMI 2 TIMI 3
DP group (n = 60)
Control group (n = 56)
p value
55.9 ± 13.9 51 (85%) 32 (53%)
58.8 ± 14.5 40 (71%) 31 (56%)
0.265 0.113 0.782
21 (36%) 12 (20%) 40 (68%)
30 (54%) 12 (21%) 32 (57%)
0.086 1.000 0.254
181.7 ± 33.2 131.4 ± 92.9 42.6 ± 11.4 113.5 ± 34.5 52.1 ± 9.4 1.44 ± 0.30 339.3 ± 189.2
191.6 ± 40.9 128.9 ± 89.3 41.9 ± 9.6 123.0 ± 36.8 49.0 ± 11.2 1.53 ± 0.37 327.8 ± 209.5
0.165 0.886 0.746 0.170 0.104 0.135 0.772 0.086
38 (63%) 14 (23%) 8 (13%)
44 (80%) 9 (16%) 2 (4%)
32 (53%)
31(56%)
4 (7%) 24 (40%)
5 (9%) 19 (35%)
3.4 ± 0.4 0.17 ± 0.27 95.5 ± 7.4
3.3 ± 0.5 0.18 ± 0.38 94.7 ± 11.1
40 (67%) 11 (18%) 9 (15%)
41 (76%) 6 (11%) 7 (13%)
0.782
0.163 0.854 0.642 0.466
DP = distal protection; HDL = high density lipoprotein; LDL = low density lipoprotein; EF = ejection fraction; LVWMSI = left ventricular wall motion score index; CAD = coronary artery disease; PCI = percutaneous coronary intervention; MLD = minimal lumen diameter; DS = diameter stenosis; TIMI = thrombolysis in myocardial infarction.
DP group (n = 60)
Control group (n = 56)
p value
3.4 ± 0.4 3.1 ± 0.4 10.0 ± 7.6 0 100 (60/60)
3.3 ± 0.5 3.0 ± 0.5 10.5 ± 8.3 1 100 (56/56)
0.163 0.332 0.747 – 1.000
1.22 0 (0/60) 26.7% (16/60) 5.0% (3/60)
1.16 1.8 (1/56) 23.2% (13/56) –
0.875 0.761 0.458
107.8 ± 25.4
94.5 ± 18.9
0.156
1 (2%) 1 (2%) 58 (96%)
1 (2%) 9 (17%) 43 (81%)
3 (5%) 18 (30%) 39 (65%)
17 (32%) 16 (30%) 20 (38%)
0.016
0.001
PCI = percutaneous coronary intervention; DP = distal protection; MLD = minimal lumen diameter; DS = diameter stenosis; GP = glycoprotein; TIMI = thrombolysis in myocardial infarction; TMP = TIMI myocardial perfusion.
groups. Peak cardiac enzyme after revascularization (CK-MB; 266.4 ± 180.2 μg/ml vs. 311.9 ± 174.0 μg/ml, p = 0.188) was similar in both groups. There were no significant differences between the two groups in the rates of implanted stents per patient (1.22 vs. 1.16, p = 0.875), direct stenting (0 (0%) vs. 1 (1.8%), p = 0.761), post-dilation (16 (26.7%) vs. 13 (23.2%), Table 3 Coronary flow parameters and phasic coronary flow patterns
Heart rate (pulse/min) Baseline mean blood pressure (mm Hg) Hyperemic mean blood pressure (mm Hg) Flow velocity parameters bAPV (cm/s) hAPV (cm/s) CFR bMVRI (mm Hg cm− 1 s) hMVRI (mm Hg cm− 1 s) Coronary phasic flow patterns bDDT (ms) hDDT (ms)
DP group (n = 35)
Control group (n = 33)
p value
77.7 ± 16.1 76.6 ± 11.8
78.2 ± 16.5 84.2 ± 18.1
0.670 0.043
74.9 ± 12.5
84.0 ± 17.7
0.017
23.2 ± 11.5 39.2 ± 16.7 1.80 ± 0.64 4.18 ± 2.22 2.38 ± 1.39
18.0 ± 6.9 30.6 ± 10.8 1.80 ± 0.60 5.34 ± 2.25 3.11 ± 1.32
0.029 0.014 0.979 0.036 0.030
669 ± 262 751 ± 246
519 ± 282 616 ± 269
0.026 0.035
DP = distal protection; bAPV = baseline averaged peak velocity; hAPV = hyperemic averaged peak velocity; CFR = coronary flow reserve; bMVRI = baseline microvascular resistance index; hMVRI = hyperemic microvascular resistance index; bDDT = baseline diastolic deceleration time; hDDT = hyperemic diastolic deceleration time.
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Table 4 Clinical outcome and left ventricular function at six months
Composite MACE at 30 days Death TVR Reinfarction Composite MACE at 6 months Death TVR Reinfarction
control group (679± 262 vs. 519 ± 289 ms, p= 0.035; and 751 ± 246 vs. 616 ± 269 ms, p= 0.035, respectively) (Table 3).
DP group (n = 54/60)
Control group (n = 52/56)
p value
2
2
0.757
– 1 1 4
2 0 0 5
– 3 1
2 2 1
0.400
Left ventricular function at DP group 6 months (n = 48/60)
Control group (n = 47/56)
p value
Ejection fraction (%) LVWMSI ΔEjection fraction (%) ΔLVWMSI
54.6 ± 10.3 1.40 ± 0.32 5.65 ± 8.64 −0.09 ± 0.26
0.239 0.118 0.832 0.498
58.1 ± 11.4 1.28 ± 0.27 6.18 ± 9.46 − 0.13 ± 0.23
DP = distal protection; MACE = major adverse cardiac event; TVR = target vessel revascularization; LVWMSI = left ventricular wall motion score index; ΔEjection fraction = difference between 6 months follow-up ejection fraction and baseline ejection fraction; ΔLVWMSI = difference between 6 months follow-up LVWMSI and baseline LVWMSI.
p = 0.458) and time from hospital arrival to stent implantation (339.3 ± 189.2 min vs. 327.8 ± 209.5 min, p = 0.772). In the DP group, 3 cases of the temporary occlusion balloon reinflation for further revascularization procedures were performed, two of which were for high-pressure ballooning and the other one for provisional ballooning of a big side branch. After primary PCI, achievement of final TIMI grade 3 was more frequent in the DP group than in the control group (58 (96%) vs. 43 (81%), p = 0.016). The proportion of patients with TMP grade 3 after revascularization was significantly higher in the DP group than in the control group (39 (65%) vs. 20 (38%), p = 0.001). The proportion of TMP grade 3 remained higher in the DP group than in the control group when TMP grades were analyzed among the patients subgroup achieving TIMI grade 3 (39 (67%) vs. 20 (47%), p = 0.007). 3.3. Coronary flow velocity parameters and phasic coronary flow velocity patterns There were no significant differences in heart rate and baseline mean aortic blood pressure between the two groups. After primary PCI, the baseline APV and hyperemic APV were significantly higher in the DP group than in the control group (23.2± 11.5 vs. 18.0 ± 6.9 cm/s, p = 0.029; and 39.2± 16.7 vs. 30.6± 10.8 cm/s, p= 0.014, respectively). Baseline and hyperemic MVRI were significantly lower in the DP group than in the control group (4.18 ± 2.22 vs. 5.34 ± 2.25 mm Hg cm− 1 s, p = 0.036; and 2.38 ± 1.39 vs. 3.11 ± 1.32 mm Hg cm− 1 s, p = 0.030, respectively). However, the two groups did not have any significant differences in CFR. The baseline and hyperemic DDT were significantly longer in the DP group than in the
3.4. Late clinical events: Six-month clinical outcome and left ventricular function Table 4 summarizes 1 and 6 months clinical outcomes and left ventricular function changes. At six months secondary end points were reached in 90.0% of the DP group and 92.9% of the control group. The rates of MACE at 6 months were 7.4% and 9.3% in each group. There were no significant differences in composite endpoints of death, TVR and reinfarction between the two groups (p = 0.40) at both 30 days and 6 months. Improvement of left ventricular function (ΔEjection fraction between baseline and 6 months; 6.18± 9.46% vs. 5.65± 8.64%, p = 0.832) and regional wall motion abnormalities (ΔLeft ventricular wall motion score index between baseline and 6 months; −0.13 ± 0.23 vs. −0.09± 0.26, p = 0.498) were similar in both groups. Randomized treatment modalities also did not affect the left ventricular function improvement. 4. Discussion The mechanism of suboptimal myocardial salvage after primary angioplasty of acute myocardial infarction is multifactorial and has not yet been fully elucidated. Prolonged cessation of coronary blood flow leads to permanent ischemic damage of myocardial microstructure. Subsequent restoration of normal blood flow to the myocardium produces the so-called “reperfusion injury” by a variety of mechanisms [19–21]. Finally, the atheroembolism during the revascularization procedure may add to the extent of myocardial damage [9]. To optimize the salvage of infarct myocardium with revascularization, many trials have aimed at reducing the atheroembolic injury using a variety of innovative devices to filter these microemboli [10–12]. The present study was also designed with this concept in mind. The present study demonstrates the preservation of distal microcirculation during primary PCI using a distal protection device in STEMI patients. TMP grade measured immediately after PCI showed a significantly higher incidence of TMP grade 3 in the DP group. Even among the subgroup of patients achieving TIMI flow grade 3, the distal protection device successfully protected microvasculature from microembolism during the primary PCI. Patients in the DP group had higher APV and lower MVRI after elimination of epicardial coronary occlusion. This observation again underlines the fact that the distal protection device protects the microvascular structure of infarct myocardium from further damage. Intravascular plugging of necrotic cell debris, thrombotic and atheromatous material combined with ischemic injury interfere with coronary blood flow and decrease the coronary flow velocity and increase microvascular resistance [22]. Therefore higher APV and lower MVRI in the patients of the DP group imply that their microvascular integrities are preserved well from microembolism during
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primary PCI. Consistent results were demonstrated by REMEDIA (Randomized evaluation of the effect of mechanical reduction of distal embolization by thrombus aspiration in primary and rescue angioplasty) study using contrast echocardiogram. In the study, the patients treated with a thrombus aspiration filter device revealed significantly lower contrast score index and contrast defect, which suggests the beneficial effects of distal embolization reduction [23]. Furthermore, in extensively damaged myocardium of AMI, the available intravascular space is considerably decreased and the microvascular resistance is elevated such that coronary blood flow rapidly fills the intact intramyocardial blood pool during the diastolic phase with a rapid subsequent reduction [22]. This results in a rapidly decelerating diastolic flow and an early systolic retrograde flow or a decreased systolic flow. Kawamoto et al. [24] and Akasaka et al. [25] advocated that SAPV less than 6.5 cm/s, or early systolic flow reversal and DDT less than 600 ms immediate after PCI indicates a low probability of improvement in the left ventricular function. Thus, the significantly longer DDT in the DP group (versus the control group) suggests a favorable pattern of reduction in myocardial injury. EMERALD [26] (Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris) study, however, showed that the distal embolic protection in primary PCI of AMI did not preserve microvascular integrity immediate after PCI, which were different results from our study. Some likely explanations are as follows. First, the patients randomized to receive distal protection in EMERALD study received complete distal protection during PCI only in 79% of patients, because 21% of these patients underwent some additional procedures after the retrieval of distal occlusion balloon or received incomplete protection during PCI. Secondly, a large proportion of glycoprotein IIb/IIIa platelet receptor inhibitor usage in EMERALD study may have possibly diminished the superiority of distal protection devices over PCI only. Because platelet and fibrin plugging is an important contributor to the pathogenesis of distal microembolization [6,27,28], administration of glycoprotein IIb/IIIa platelet receptor inhibitor in PCI only group may reduce the potential benefit of the distal protection device. Thirdly, EMERALD study patients had less jeopardized myocardium compared to those in the present study. The length of time from onset of symptoms to reperfusion in EMERALD study was shorter (233 min in distal the protection group, 211 min in the control group, p = 0.02) than that of the present study. The time interval to reperfusion is an important factor in rescuing ischemic myocardium in AMI [29]. Low risk myocardium may diminish these differences. Our study, however, also did not demonstrate the improvement of clinical outcome in the DP group that is compatible with the results of EMERALD study. While the distal protection device preserved the microvascular integrity immediate after PCI, that preservation may not be sufficient to be linked to the improvement in left ventricular function.
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Considering the study results in PCI of degenerated saphenous vein grafts [30,31], these might be due to incomplete protection of side branches (e.g., diagonal and obtuse marginal branches). This can be potentially overcome by proximal occlusion system [32]. Paradoxically, the additional time required for distal protection procedure might increase the infarct size. PercuSurge distal occlusion balloon system occludes the distal blood flow completely during the procedure which may cause unintentional damage to the myocardium. Finally another mechanism besides distal microembolization such as reperfusion injury, local inflammatory cytokines and endothelial dysfunction etc. should be considered in conjunction with distal protection for improving clinical outcomes. 4.1. Study limitations Though our study was designed as prospective, the small number of patients is a major limiting factor. The sample size was calculated on assumptions related to any improvement of microvascular integrities, instead of the secondary end point of the trial. This allowed us to enroll fewer patients at the cost of a reduced power with regard to the secondary end point. Small sample size might be underpowered to demonstrate the efficacy of distal protection in clinical outcome improvement. 5. Conclusion Adjunctive therapy with distal protection device in primary PCI of STEMI patients preserves microvascular integrity when compared to isolated PCI. It appears that preservation of microvascular integrity by distal protection device may not be sufficient to result in an improvement in clinical outcomes. References [1] Zahn R, Schiele R, Schneider S, et al. Primary angioplasty versus intravenous thrombolysis in acute myocardial infarction: can we define subgroups of patients benefiting most from primary angioplasty? Results from the pooled data of the Maximal Individual Therapy in Acute Myocardial Infarction Registry and the Myocardial Infarction Registry. J Am Coll Cardiol 2001;37:1827–35. [2] Andersen HR, Nielsen TT, Rasmussen K, et al. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 2003;349:733–42. [3] Iwakura K, Ito H, Nishikawa N, et al. Early temporal changes in coronary flow velocity patterns in patients with acute myocardial infarction demonstrating the “no-reflow” phenomenon. Am J Cardiol 1999;84:415–9. [4] Piana RN, Paik GY, Moscucci M, et al. Incidence and treatment of ‘noreflow’ after percutaneous coronary intervention. Circulation 1994;89:2514–8. [5] Kotani J, Nanto S, Mintz GS, et al. Plaque gruel of atheromatous coronary lesion may contribute to the no-reflow phenomenon in patients with acute coronary syndrome. Circulation 2002;106:1672–7. [6] Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease. Circulation 2000;101:570–80.
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