The Evolving Role of Glycoprotein (GP) IIb/IIIa Receptor Blockade During Percutaneous Coronary Intervention of Saphenous Vein By

Percutaneous coronary intervention (PCI) has improved the treatment of coronary artery disease. However, unlike native coronary arteries, progress in the percutaneous intervention of saphenous vein bypass grafts (SVBG) has been disappointing, often complicated by distal embolization of atherothrombotic debris and resulting in high periprocedural morbidity.1 SVBG interventions have an increased incidence of major adverse clinical events (MACE) compared to native coronary interventions, with approximately 20% of vein graft interventions complicated by myocardial infarction or no-reflow phenomenon.2,3 PCI of native coronary arteries has seen a reduction in periprocedural MACE and improvement in long-term clinical outcomes with adjunctive platelet glycoprotein (GP) IIb/IIIa receptor inhibition.4 This same benefit has not been appreciated with saphenous vein graft interventions.4,5 We review the morphological features complicating saphenous vein graft disease, the current literature regarding GP receptor blockade in vein graft interventions and potential future therapies. Histopathology of SVBG disease. Histopathology of saphenous vein graft disease is influenced by the age of the graft. For example, SVBG occlusion within the first month is often due to thrombus.6 From 1 month to approximately 1-year, intimal hyperplasia is the predominant cause of disease.7 Beyond 1-year, atherosclerosis is the predominant cause of disease with clinical implications predominantly observed after approximately 5 years. For the remaining discussion, the focus of histopathology will be in older vein grafts, often defined as > 5 years old.8 Saphenous vein graft plaque morphology likely contributes to the worse outcomes associated with their percutaneous intervention. Atherosclerosis in vein grafts is often referred to as “gruel,” which describes a soft and friable plaque that is rich in necrotic debris, cholesterol crystals, blood elements, inflammatory cells and foam cells.9–12 Morphologically, plaques within vein grafts tend to have less calcification, lack a fibrous cap, and are more diffuse, concentric and friable than those within native coronaries.13 Furthermore, SVBGs appear to have less focal compensatory enlargement (“Glagov remodeling”).14 These morphological features may explain in part the increased downstream embolization encountered during coronary intervention of vein grafts. Further complicating vein graft atherosclerosis is a propensity toward superimposed thrombus formation that is influenced by multiple mechanisms. First, harvesting of the venous conduits causes disruption of the endothelial cell layer, promoting platelet and neutrophil adherence to the luminal surface as well as activation of the extrinsic coagulation system.15,16 Moreover, the presence of intact valves and anastomotic strictures leads to blood stasis.16 There is often a mismatch between the larger vein conduit and the smaller artery to which it is anastomosed, which also contributes to slow flow in the vein graft. These factors, coupled with increased sensitivity to circulating vasoconstrictors and the decreased antithrombotic properties of the venous system, promote a prothrombotic milieu.16,17 This propensity toward thrombus formation has been demonstrated by angioscopy, which showed that up to 70% of vein graft lesions undergoing treatment had thrombus.18 Ultimately, the nature of vein graft atherosclerosis and amplified thrombus formation contribute to the increased complication rates of coronary intervention in vein grafts. Distal embolization during angioplasty. There is ample evidence that distal embolization routinely occurs during angioplasty and stent deployment.19 First, transcranial Doppler of the middle cerebral artery repeatedly demonstrated echogenic material during carotid stent placement.20 More importantly, atherosclerotic debris is frequently retrieved during angioplasty with the use of a distal protection device.13,21,22 Due to the variety of criteria used for defining distal embolization, a true incidence is not available; however, the literature reports a range of 5–14% during angioplasty of vein graft lesions ranging from 7.8–10 years.1,23,24 The morphology of vein graft plaques likely contributes to this high occurrence of distal embolization. For example, at autopsy after SVBG intervention, emboli were associated with plaque rupture, plaque extrusion and medial dissection. All of these are commonly encountered during vein graft interventions.25 In addition, the presence of thrombus on angiography in the target vessel has been associated with distal embolization (39% in distal embolization patients compared with 14% in patients without embolization; odds ratio = 3.95; 95% confidence interval, 1.80–8.66).1 As previously stated, saphenous vein grafts have a propensity for superimposed thrombus formation. Recognized predictors of distal embolization of saphenous vein graft interventions include the presence of diffuse disease, plaque volume and thrombus.23 Although a causal relationship has never been unequivocally demonstrated, the increased incidence of MACE observed during percutaneous intervention of a saphenous vein graft is most likely attributable to distal embolization.1–3,21,26,27 In one series of vein graft interventions, distal embolization was associated with an approximately 10-fold increase in the risk of the composite clinical endpoint of death, myocardial infarction, repeat intervention and emergency coronary artery bypass graft surgery.1 Furthermore, length of hospital stay and 1-year incidence of myocardial infarction were increased in the distal embolization group. GP receptor blockade trials during SVGB intervention. The same level of success of GP IIb/IIIa inhibitors in native coronary arteries has not been observed in SVBG interventions.4,5 GP IIb/IIIa inhibitors have been studied in patients undergoing percutaneous revascularization of vein grafts (Table 1). Abciximab was studied in 101 patients in the Evaluation of IIb/IIIa Platelet Receptor Antagonist 7E3 in Preventing Ischemic Complications (EPIC) trial who were treated for narrowing of saphenous vein grafts, with 38 in the bolus (0.25 mg/kg) plus infusion (10 µg/min for 12 hours) group, 34 in the bolus group (0.25 mg/kg) and 29 in the placebo group. In the patients treated with a bolus plus infusion, distal embolization occurred in only 2%, versus 18% of the placebo group (p = 0.017), while a trend toward reduction in early large non-Q wave acute myocardial infarction (2% versus 12%, respectively; p = 0.165) was also reported. Nonetheless, this did not translate into improved clinical outcomes, as the occurrence of 30-day and 6-month composite endpoint was similar among the 3 treatment groups.28 In a retrospective study, Mathew et al. reported on 133 patients who underwent intervention of a saphenous vein graft with abciximab in comparison to 210 who were treated without abciximab.29 Angiographic and procedural success rates were similar with or without the use of abciximab (89% versus 92%, respectively; p = 0.15, and 85% versus 91%, respectively; p = 0.12). The in-hospital MACE rate was similar between the abciximab and no abciximab groups (9% versus 5%, respectively; p = 0.17). Roffi et al. performed a pooled analysis of SVBG interventions in 5 randomized trials involving intravenous GP IIb/IIIa inhibitors.5 The study population consisted of 627 patients undergoing SVBG intervention; there was follow-up for 605 patients, 389 of whom were randomly assigned to IIb/IIIa therapy (51% with abciximab and 49% with eptifibatide) and 216 of whom were assigned placebo. At 30 days, MACE occurred in 16.5% of the treatment group and 12.6% of the placebo group (odds ratio, 1.38; 95% confidence interval, 0.85–2.24; p = 0.18). At 6 months, MACE occurred in 39.4% of the treatment group and 32.7% of the placebo group (hazard ratio, 1.29; 95% confidence interval, 0.97–1.72; p = 0.07) (Figure 1). Furthermore, when analyzed individually, no trial favored the use of GP IIb/IIIa (Figure 2). Non-traditional administration of GP receptor blockade or combination GP IIb/IIIa therapy during SVBG interventions A. Local administration of a GP IIb/IIIa receptor blocker. Higher concentrations of GP IIb/IIIa receptor blockers via local administration may theoretically be more efficacious by inhibiting platelets located within the thrombus and promoting an overall greater dethrombotic effect than intravenous administration.30 Abciximab has also been shown to have additional anti-inflammatory and antithrombotic effects via the blockade of platelet-leukocyte interactions, CD11b/18 (Mac-1)/av/b3 (vitronectin) expression, and sCD40L release.31,32 However, the anti-inflammatory and antithrombotic effects are dependent on the level of platelet inhibition, with high levels displaying an inhibitory effect. In contrast, at lower levels of receptor inhibition, the antagonists may actually enhance inflammation through the induction of platelet-leukocyte aggregates33 and increases in serum levels of CD40L.34 To date, few studies have examined the role of intracoronary GP IIb/IIIa receptor blockade in SVBG interventions. Local administration of abciximab has been tested in a pilot study of 58 patients undergoing treatment of 9.0-year-old vein grafts.35 Abciximab (0.25 mg/kg) was administered by local delivery catheter before percutaneous intervention for de novo SVBG stenoses followed by intravenous infusion. All patients (n = 58) had > 60% stenosis and Thrombolysis in Myocardial Infarction (TIMI) grade > 0 flow in an SVBG of 3–4 mm in diameter. Primary endpoints were change in percent diameter stenosis, TIMI thrombus grade and TIMI flow grade after local drug delivery. Median percent diameter stenosis improved from 69% to 45% (p = 0.0001) after local delivery, and TIMI thrombus grade > 1 incidence was reduced from 68% to 34% (p = 0.0001). TIMI flow grade was not significantly affected (p = 0.12). Seven patients developed an acute myocardial infarction in association with the treatment, defined as creatine kinase MB level greater than 3 times normal or greater than 50% of the pre-procedural value. Therefore, the authors of this study concluded that local abciximab delivery before percutaneous SVBG intervention significantly reduced thrombus burden, improved percent diameter stenosis and resulted in excellent acute procedural results. This study suggests that higher local drug delivery may be needed to achieve improved outcomes in SVG intervention. Despite these promising results, the study did not follow clinical endpoints nor was a control group included. B. Delayed SVBG intervention after pretreatment with a GP IIb/IIIa receptor blocker. Delayed SVBG intervention after pretreatment with a GP IIb/IIIa receptor blocker may allow for endogenous lysis of thrombus prior to intervention. Robinson et al. described 5 cases with multivessel coronary artery disease, including a culprit saphenous vein graft stenosis with associated massive thrombus.36 Patients transferred for angiography were treated with heparin. At angiography, the thrombus burden was felt to be too large for intervention at an acceptable risk. Therefore, each patient received a bolus of abciximab (0.25 mg/kg) followed by a 12-hour infusion at 10 µg/min. No further heparin was given until the angioplasty procedure. The next day, repeat angiography demonstrated a major reduction in the thrombus score and the presence of TIMI 3 flow in each vein graft lesion. Angioplasty with stent insertion was then successfully performed with no episodes of distal embolization or no-reflow phenomenon. C. GP IIb/IIIa receptor blockade and combined thrombolytic therapy prior to SVBG intervention. Theoretically, as demonstrated via an in vitro flow circulation model, the addition of GP IIb/IIIa blocker to a thrombolytic may be expected to block platelet-fibrin interactions that lead to clot retraction, thus maintaining a fibrin architecture that is more susceptible to lysis.37 Despite reports of local infusion of thrombolytic agents in the treatment of SVBG occlusion,38,39 randomized controlled studies on combination therapy of GP IIb/IIIa receptor blockers are presently lacking. D. Distal protection devices and GP IIb/IIIa receptor blockade. The conflicting results observed with the use of GP IIb/IIIa receptor blockers during SVBG interventions suggest that embolized debris, along with platelet-mediated thromboembolism, may play an important role in the poor outcomes associated with PCI of SVBG lesions. In this regard, the use of distal embolization protection devices has been suggested as an adjunctive therapy during SVBG interventions. The Saphenous Vein Graft Angioplasty Free of Emboli Randomized (SAFER) trial by Baim et al.21 showed a significant reduction in distal embolization and the triple endpoint during PCI of SVBG with the use of a balloon occlusive distal embolic protection device, illustrating a significant advance in SVBG intervention. Approximately 57% of patients were preselected for use of a platelet GP IIb/IIIa receptor blocker in the GuardWire arm and 58% in the control arm. The GP IIb/IIIa receptor group had a higher incidence of MACE than patients selected not to receive IIb/IIIa blockers. This was likely due to operator selection for higher-risk lesions. However, when a GP IIb/IIIa receptor blocker was used, a reduction in MACE was observed with the GuardWire distal protection (10.7% versus 19.4%, respectively; p = 0.008). Additional distal protection devices using filters and proximal conduit occlusion may also provide benefit in the above clinical scenario. Stone et al. recently examined the FilterWire EX in the FilterWire EX Randomized Evaluation (FIRE) trial and demonstrated that the filter-based emboli protection catheter is equally effective in this setting, and noninferior to the balloon occlusion device.40 Some of these devices are already being tested in randomized clinical trials. One potential problem that persists with distal protection devices is the finite lower limit in the size of particles that can be captured with smaller particles escaping through the filter. Some of these particles might theoretically be eliminated with GP IIb/IIIa receptor blockade. Limitations of the use of GP IIb/IIIa inhibitors for SVBG interventions. As mentioned previously, the histopathology of SVBG disease may make the use of GP IIb/IIa receptor blockers more challenging and less efficacious than in native coronary artery interventions. Although SVBG interventions promote platelet activation, the presence of a large burden of atheroembolic material13 may decrease the efficacy of antiplatelet therapies in the prevention of distal embolization. The propensity for a large distal embolization burden of atherothrombotic debris, which often occurs during SVBG intervention, appears to also limit the efficacy of GP IIb/IIa receptor blockers by overcoming the ability of these agents to protect the distal vasculature. This is a likely explanation for the negative clinical results of GP IIb/IIIa receptor blockers in SVGB interventions. Conclusion. Our current understanding of the morphological features of plaque within SVBGs and the pathophysiology of distal embolization during intervention define a major role for platelets and platelet activation. Therefore, the initial enthusiasm for adjunctive use of IIb/IIIa inhibitors is understandable. Nonetheless, current research analyzing clinical outcomes in this group of patients has not proven beneficial (Table 1). This does not imply that there is no role for GP IIb/IIIa inhibitors in PCI of SVBG. In order to fully understand the potential role of GP receptor blockade in PCI, the current framework of this complex process as well as the potentially promising results of the small trials should be extended. Novel delivery methods (intracoronary, prolonged infusions) or combination cocktails (thrombolytics, GP IIb/IIIa inhibitors) should be evaluated in the setting of a distal protection device before abandoning the use of these drugs for SVBG intervention.

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