Abstract
The outcome of patients with acute myocardial infarction (AMI) is critically dependent on adequate reperfusion at the tissue level. Primary percutaneous coronary intervention (PCI) achieves full patency of the infarct-related vessel in >90% of the patients with AMI. Despite the restoration of large-vessel flow, tissue perfusion in area at risk frequently continues to be compromised. To optimize microvascular reperfusion and clinical outcomes, additional measures are needed. Thus far, mechanical approaches to improve distal perfusion, such as the use of distal protection devices, have not been shown beneficial. Among the pharmacological approaches, high-dose adenosine infusion holds promise but has to be proved by further clinical studies. Glycoprotein IIb/IIIa receptor blockade with abciximab has a documented efficacy in improving microvascular flow, contractile recovery, and patient survival after primary PCI in AMI. In addition to the inhibition of platelet aggregation, prevention of pro-inflammatory heterotypic platelet interactions may contribute to the beneficial effect of this drug.
Illusion of TIMI grade 3 flow
The treatment strategy for acute myocardial infarction (AMI) is rapidly evolving. Early and complete reperfusion has become the main goal of treatment. Restoration of unimpeded flow through the occluded coronary artery [i.e. thrombolysis in myocardial infarction (TIMI) grade 3 flow] is the prerequisite for survival benefit and recovery of contraction in the infarct area.1–3 Thus, until recently, TIMI grade 3 flow was considered to be predictive of optimal clinical benefit. However, it is becoming increasingly clear that restoration of large-vessel patency alone does not suffice to achieve the best outcome.
Despite the restoration of large-vessel flow, tissue perfusion in the area at risk frequently continues to be compromised, as shown by myocardial contrast echocardiography (MCE),4,5 flow velocity measurements,6–10 and assessment of TIMI frame counts11,12 or myocardial blush.13,14 Persistent microcirculatory impairment is associated with poor recovery of contractile function4–10 and adverse clinical outcomes.4,11–14 Thus, restoration of large-vessel patency does not mean complete perfusion recovery, and perfusion of the microvasculature is an additional prerequisite for obtaining optimal recovery.
Adjunctive therapies to improve microvascular reperfusion
The extent of microvascular perfusion deficits in the presence of TIMI grade 3 flow varies among patients4–14 and is a predictor of myocardial recovery4–10 and clinical outcomes.4,11–14 Therefore, the treatment for AMI should include attempts to correct microvascular perfusion as well as large-vessel perfusion.
Mechanical approaches
Since the early days of primary percutaneous coronary intervention (PCI), the fate of the occlusive thrombus material that is destructed by primary PCI has been a matter of concern. Systematic evaluation revealed angiographic evidence of distal embolization in 9–15% of the patients after primary PCI for AMI,15–17 but the true incidence of distal embolization may be considerably higher as suggested by autopsy studies18 and experience with distal protection devices.15–17 Distal embolization carries an increased risk of poor clinical outcomes; in a recent study, it was associated with an eight-fold increase in 5-year mortality.16
On the basis of these findings, distal embolization of plaque and thrombus material is considered to be a major cause for insufficient reperfusion, despite a fully patent infarct-related artery. Hence, it was hypothesized that distal protection devices that prevent embolization during primary PCI may improve distal perfusion.
This concept, however, could not be proved in randomized studies. The first of these trials was the Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberalized Debris (EMERALD) study on distal balloon occlusion and aspiration.19 EMERALD study randomized 501 patients to distal protection or usual care. Visible debris that otherwise would have entered the distal circulation could be removed in 73% of the patients of the study group. Nevertheless, neither the primary endpoint ST-segment resolution nor any of the secondary endpoints including myocardial blush showed any significant benefit of distal protection when compared with usual care.
Concurrent results were obtained in the randomized controlled Protection Devices in PCI Treatment of Myocardial Infarction for Salvage of Endangered Myocardium (PROMISE) study.20 PROMISE study evaluated the effects of the filter wire on myocardial perfusion, as determined by the maximal blood flow velocity across the recanalized infarct-related artery. The study enrolled 200 patients with myocardial infarction (69% ST-elevation) within 48 h (median 6.9 h) after onset of pain. Adenosine-induced flow velocity in the recanalized infarct artery was 34±17 cm/s with the filter and 36±20 cm/s without (P=0.46). Infarct size measured by magnetic resonance imaging was 12±9% of the LV with the filter and 10±9% without (P=0.33). Hence, the filter did not improve reperfusion or reduce infarct size after primary PCI. The consistent results of EMERALD and PROMISE suggest that irrespective of the technology, distal protection does not improve reperfusion after primary PCI in myocardial infarction to a clinically detectable degree.
Pharmacological approaches: adenosine
Various pharmacological approaches to improve reperfusion have been tested. These included antioxidants to mitigate reperfusion-associated oxidative stress,21 rheological agents to improve blood viscosity,22,23 and anti-inflammatory agents.24,25 However, none of the clinical trials yielded convincing results. More recently, peri-interventional administration of adenosine has received much attention. In animal models of infarction, adenosine attenuates the no-reflow phenomenon and limits neutrophil activation and reperfusion injury.26,27 A clinical study of 54 patients suggested that adenosine as adjunct to primary percutaneous transluminal coronary angioplasty (PTCA) ameliorated flow and prevented the no-reflow phenomenon.28 However, the effect of adenosine was less convincing in the adequately powered clinical trial Acute Myocardial Infarction Study of Adenosine (AMISTAD II).29 In this study, 2118 patients with evolving anterior STEMI receiving thrombolysis or primary angioplasty were randomized to a 3-h infusion either of adenosine 50 or 70 µg/kg per minute or of placebo. Clinical outcomes in patients with STEMI undergoing reperfusion therapy were not significantly improved with adenosine. Nevertheless, infarct size was reduced with the 70-µg/kg per minute adenosine infusion, and this finding correlated with fewer adverse clinical events. The investigators of AMISTAD concluded that a larger study limited to the 70-µg/kg per minute dose was warranted.
Pharmacological approaches: GP IIb/IIIa receptor blockade with abciximab
Previous investigations on experimental models of myocardial infarction documented the pre-eminent role of platelets in limiting blood flow during reperfusion in AMI.30 By occlusive thrombus formation, distal embolization of small aggregates, and release of vasoconstrictive mediators, platelets interfere with both large-vessel patency and microvascular flow.30
The effect of abciximab on microvascular reperfusion was investigated in the first 200 patients enrolled in the ISAR-2 (Intracoronary Stenting and Antithrombotic Regimen-2) trial (Figure 1).9 After 2 weeks, patients in the abciximab arm showed a significantly improved recovery of peak-flow velocity (as measured using the Doppler wire) in the occluded coronary artery when compared with that of patients in the conventional treatment arm [mean increase in peak-flow velocity within 14 days (95% CI): 18.1 (13.6–22.6) cm/s vs. 10.4 (5.4–15.4) cm/s; P=0.024; Figure 1]. As quantitative coronary angiography did not reveal any difference in angiographic outcome between the two treatment groups, the beneficial effect of abciximab reflected improvement in microvascular function.
The recovery of microvascular function was correlated with a significant improvement in wall motion in patients receiving abciximab when compared with that of the control group. Thus, the improvement of wall motion index in the infarct region was significantly greater in patients assigned to abciximab than that in those on heparin alone [mean increase within 14 days: 0.44 (0.29–0.59) SD/chord vs. 0.15 (0.00–0.30) SD/chord; P=0.007; Figure 1].9 At 14-day follow-up, the abciximab-treatment group had a higher global LV ejection fraction than that of the heparin-treatment group [62 (59–65)% vs. 56 (53–59)%; P=0.003). This finding is consistent with other studies, illustrating a close relationship between the recovery of perfusion and contractile function in infarct region.4–10
ISAR-2 trial was the first study demonstrating that in AMI, abciximab has important effects beyond the maintenance of large-vessel patency. It improves the coronary perfusion recovery at the level of the distal vascular bed and concomitantly enhances the restoration of LV function in the infarct area. Several, more recent studies have confirmed the effect of abciximab on reperfusion of the distal vascular bed.
Mulumudi et al.31 used myocardial blush to study the effect of abciximab on myocardial microcirculation following PTCA and/or stenting for AMI. They found that 74% of patients receiving abciximab (n=27) had moderate-to-normal blush when compared with 45% of those in the control group (n=20). This effect was particularly striking in diabetics, almost two-thirds of diabetics receiving abciximab had normal blush when compared with no diabetics in the control group.
Petronio et al.32 investigated the effect of abciximab and adenosine on microvascular integrity and LV functional recovery in 47 AMI patients undergoing PTCA. When compared with controls receiving conventional therapy, MCE revealed an improvement in microvascular perfusion in the treatment groups, both immediately after PTCA and at 48 h. At 30 days, only abciximab remained superior to conventional treatment. Microcirculation recovery in the abciximab group translated into an improvement in wall motion at 3 months, indicating an improved recovery of LV function.
In a later study by Petronio et al.,33 the effect of abciximab on microvascular integrity and LV functional recovery was studied in 31 AMI patients (<6 h) treated with primary PTCA. Patients randomized to abciximab showed significant improvements in measures of myocardial reperfusion (corrected TIMI frame count, 23±4 vs. 30±9 frames; P<0.05). In addition, microvascular integrity, measured using MCE, was preserved both in the short-term [77 vs. 55% (P<0.01) after PTCA and 86 vs. 50% (P<0.005) after 48 h] and at 1-month follow-up (86 vs. 54%; P<0.001). Abciximab patients also showed better recovery of LV function, as indicated by an improved wall motion score index (1.4±0.3 vs. 1.5±0.2; P<0.05) and increased LV ejection fraction (53+7 vs. 48.5±5%; P<0.001). The authors concluded that in AMI patients treated with PTCA, abciximab can preserve microvascular integrity and thus assist LV function recovery.
Molecular mechanisms of abciximab effect
In contrast to other GP IIb/IIIa blockers, abciximab is non-specific and also blocks other integrins, such as Mac-1 (αM/β2)34 and the vitronectin receptor (αV/β3).35 In the absence of conclusive clinical studies on the use of the more specific GP IIb/IIIa blockers in the setting of AMI,36 the contribution of the non-GP IIb/IIIa-dependent receptor blockade to clinical effects of abciximab remains unclear. Nevertheless, experimental studies suggest that Mac-1 and vitronectin receptors play a key role during ischaemia and reperfusion (discussed subsequently).
Inhibition of thrombus formation
GP IIb/IIIa is a central receptor for homotypic and heterotypic platelet interactions.37 Most importantly, the final common pathway in platelet aggregation involves fibrinogen bridging between platelet GP IIb/IIIa receptors.37 By effectively blocking this receptor, abciximab prevents platelet aggregation.37 In the setting of AMI, abcixmab not only reduces ongoing platelet-thrombus formation at the culprit lesion and distal embolization of platelet microemboli but also other consequences of platelet aggregation, such as release of vasoconstrictive mediators38 and shedding of pro-thrombotic platelet-derived microparticles.39
Inhibition of heterotypic platelet-dependent cell interactions
During reperfusion, the interaction between platelets, leukocytes, and endothelial cells also has important effects on microvascular function. In this setting, P-selectin-mediated tethering of platelets to activated endothelium occurs and subsequent firm adhesion is caused by the interaction of GP IIb/IIIa-bound fibrinogen with endothelial vitronectin receptors and intercellular adhesion molecule-1 (ICAM-1).40,41 Through stimulation by CD40 ligand (CD40L) and platelet-bound interleukin-1 activity, binding of activated platelets to endothelial cells results in the expression of monocyte chemoattractant protein-1 and ICAM-1 via a nuclear factor-κB-dependent mechanism.40,41 Activated platelets thereby modulate chemotactic and adhesive properties of endothelial cells and direct leukocyte attachment; this has been demonstrated in cell culture studies.42
Platelets can also directly support leukocyte adhesion. Heterotypic interactions of endothelium-bound platelets appear to play an important role in the recruitment of leukocytes to the site of vascular injury.43 These involve the primary attachment of platelets to myeloid leukocytes by interactions between platelet P-selectin and P-selectin GP ligand-1 (PSGL-1) on the leukocyte surface.44–49 Heterotypic adhesion is stabilized by the binding of Mac-1 on the leukocyte to an unknown counter-receptor on the platelet.47,49,50 This interaction is a result of Mac-1 activation, which in turn is due to tyrosine phosphorylation and mitogen-activated protein kinase activation stimulated by PSGL-1 ligation.47,51 Leukocyte activation by stimulated platelets is further enhanced by CD40L-dependent signal transduction.52In vitro, the binding of activated platelets to myeloid leukocytes induces the expression of pro-inflammatory cytokines, oxidative burst, and an increased surface expression of tissue factor and Mac-1.53–56 Mac-1 is known to play a key role in leukocyte-dependent reperfusion injury.57–59
Abundant platelet–leukocyte aggregates have been found in the peripheral blood of patients with AMI.54 GP IIb/IIIa receptor blockade with abciximab in these patients reduces platelet–monocyte interaction by decreasing the mass of platelets attached to monocytes.42 Through this mechanism, abciximab decreases Mac-1 surface expression on circulating monocytes.60 This effect is complemented by the direct Mac-1-blocking properties of abciximab. In addition, cell culture experiments have shown that abciximab can prevent firm adhesion of platelets to activated endothelial cells by blocking both GP IIb/IIIa and the vitronectin receptors.34 The inhibitory effect of abciximab on heterotypic platelet interactions during ischaemia and reperfusion has been confirmed by experiments in isolated guinea pig hearts, in which abciximab improved the recovery of contractile function.61 These studies demonstrate the functional importance of heterotypic platelet interactions during ischaemia and reperfusion.
A recently published clinical study is consistent with a beneficial effect of the attenuation of pro-inflammatory platelet–endothelium interaction. Aymong et al.62 demonstrated that abciximab can attenuate endothelial dysfunction. Using the Doppler wire, the investigators studied acetylcholine-mediated coronary blood flow in 48 patients who underwent stenting either with abciximab or without abciximab and a control group of 31 patients who did not undergo coronary intervention or receive drug therapy. Acetylcholine-induced vasodilation was significantly impaired after stenting without abciximab (41% increase in flow vs. 70% in the control group), whereas in patients treated with abciximab during the intervention, the blood flow response to acetycholine was normal (83% increase in flow). The beneficial effect of abciximab on endothelium-dependent vasodilator responses may be interpreted as a consequence of the inhibition of platelet–endothelium interactions.
Clinical relevance of improved reperfusion by abciximab
Experimental and mechanistic clinical studies suggest a beneficial effect of abciximab on reperfusion after primary PCI in acute myocardial studies. Five larger randomized clinical studies addressed the clinical relevance of this effect. These studies included RAPPORT (ReoPro and Primary Percutaneous Transluminal Coronary Angioplasty Organization and Randomized Trial),63 ISAR-2 trial,64 ADMIRAL (Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-Up),65 CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications),66 and ACE (Abciximab Carbostent Evaluation).67,68 With respect to combined endpoint of death, recurrent myocardial infarction, and target vessel revascularization at 30 days, each of these trials showed a significant benefit of abciximab over control (Figure 2). At 6 months, all point estimates for the triple endpoint favour abciximab, but statistical significance was obtained in ADMIRAL and ACE only. Nevertheless, pooled analysis reveals a significant benefit of abciximab (Figure 2).
Concerning the hard endpoints, death, and non-fatal re-infarction, a meta-analysis on abciximab for primary PCI, which also included smaller studies, was published recently.69 This meta-analysis revealed a significant reduction by abciximab in the 30-day incidence of re-infarction when compared with that of control group (1.0 vs. 1.9%; P=0.03). Most importantly, when compared with the control group, abciximab was associated with a significant reduction in 30-day mortality (2.4 vs. 3.4%; P=0.047) and long-term (6–12 months) mortality (4.4 vs. 6.2%; P=0.01). Thus, peri-interventional administration of abciximab for primary PCI affords a sustained clinical benefit with improved survival.
Conflict of interest: none declared.
Figure 1 Increase between 14-day follow-up and initial post-interventional study in papaverine-induced peak-flow velocity in the recanalized and stented infarct-related artery (left panel) and in wall motion index within the infarct region (right panel). Columns represent the mean difference. Error bars indicate the 95% CI. Error bars not including zero indicate that the change between initial study and follow-up is statistically significant at the 0.05-level. P-values above the columns refer to the difference between the two treatment groups. (Reproduced with permission from Ref. 9)
Figure 2 Meta-analysis of five major studies on abciximab during PCI for AMI. MI, recurrent myocardial infarction; TVR, target vessel revascularization.
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