There have been major advances in the field of percutaneous coronary intervention (PCI) since its introduction 30 years ago. The improved safety and outcomes can be attributed to increasing operator experience, advances in device technology and the pivotal role of adjunctive pharmacotherapy. Despite these advances, challenges remain that require further research and development. One such challenge is the treatment of thrombotic lesions. Coronary artery thrombus commonly develops following rupture of an atherosclerotic plaque and undergoes modifications in terms of size and composition over time. Thrombotic lesions are most frequently encountered in patients with acute coronary syndromes (ACS). Acute ST-elevation myocardial infarctions (STEMI) are typically associated with larger occlusive thrombus while non-ST-elevation myocardial infarctions (NSTEMI) typically have nonocclusive thrombi.1,2 PCI in the presence of intracoronary (IC) thrombus, whether it is angiographically visible or not, is accompanied by unique complications related to distal embolization and microvascular dysfunction which are associated with worse short- and long-term outcomes.3,4 Important advances have been made in adjunctive mechanical and pharmacological therapy. Nevertheless, available treatment options for dealing with thrombotic lesions are somewhat limited, as many patients still sustain distal embolization and microvascular injury. Evidence suggests that local intracoronary (IC) delivery of antithrombotic agents may be effective in treating patients with thrombotic coronary lesions by reducing complications associated with PCI. The aim of this article is to review the available literature regarding the efficacy of intracoronary administration of glycoprotein (GP) IIb/IIIa receptor antagonists and fibrinolytics as adjuncts for PCI in thrombotic coronary lesions.
Percutaneous coronary intervention in thrombotic lesions. Coronary thrombus consists of a combination of platelets, red blood cells and fibrin. Fresh occlusive thrombus is rich in platelets and loose fibrin strands, whereas older nonocclusive thrombus tends to be rich in red blood cells and fibrin.5 The clots are friable and can undergo fragmentation, either spontaneously or in response to PCI, resulting in downstream macro- or microembolization.6 It is likely that most patients undergoing PCI experience some degree of embolization. Distal macroembolization of atheromatous and thrombotic debris may be visible at coronary angiography in as many as 15% of patients presenting with STEMI.7 In post-mortem studies, as many as 80% of patients with STEMI have evidence of microembolization.8
Microemboli contribute to the development of microvascular dysfunction, which may play a role in the pathophysiology of the no-reflow phenomenon.9 In addition to embolization, microvascular dysfunction during PCI is also believed to be mediated through generation of oxygen free radicals, increased myocardial cell calcium levels, cellular and interstitial edema, endothelial dysfunction, vasoconstriction and inflammation.10 Impairment of microvascular perfusion is common following PCI in patients with STEMI and NSTEMI.10,11 As many as one-third of patients undergoing primary PCI have incomplete or partial ST-segment resolution despite “successful” reperfusion therapy. This is particularly pronounced in high-risk patients such as diabetics and elderly, in whom approximately 50% have absent or severely impaired myocardial blush despite normal epicardial blood flow.12,13 Microvascular dysfunction, as manifested by the no-reflow phenomenon observed in the cardiac catheterization laboratory, is associated with higher troponin elevations, larger infarct size, greater likelihood of heart failure, recurrent MI and death during follow up.14
Adjunctive therapies and outcomes following percutaneous coronary intervention in thrombotic lesions. The presence of coronary thrombus is an independent risk factor for procedural failure during PCI and adverse clinical outcomes.15 In the percutaneous transluminal coronary angioplasty (PTCA) era, the angioscopic presence of thrombus was reported to be associated with an approximate 9-fold increased risk of adverse events.16 Over the last two decades there has been a steady increase in the use of stents, GP IIb/IIIa inhibitors, ADP receptor antagonists, and so forth. Despite their widespread use, a review of our experience at Mayo Clinic suggests that the angiographic presence of thrombus is still associated with twice the risk of major adverse cardiovascular events.17
GP IIb/IIIa receptor antagonists are effective in reducing periprocedural myonecrosis in the setting of ACS. In the PTCA era, the “rescue administration” of GP IIb/IIIa receptor antagonists for thrombus that developed during angioplasty was shown to be effective in reducing thrombus burden and improving epicardial blood flow.18 Similarly, in an angiographic analysis from the CAPTURE (C7E3 Anti Platelet Therapy in Unstable REfractory angina) trial, treatment with adjunctive abciximab was associated with a reduction in thrombus burden during PTCA.19 Upstream use appears to improve myocardial perfusion. However, the impact of intravenously (IV) administered GP IIb/IIIa receptor antagonists on clinical outcomes in the presence of angiographically detectable coronary thrombus remains uncertain. A meta-analysis of 19 randomized trials that enrolled patients with non-ST-elevation ACS or STEMI demonstrated that these agents may reduce mortality.20 However, it is important to note that in patients with STEMI in whom the acute thrombus burden is greatest, the efficacy of GP IIb/IIIa inhibitors as an adjunct to primary stenting in regard to clinical outcomes has been variable.21-24 Also, the efficacy of stents in the presence of angiographically visible thrombus remains uncertain. In the early stent era, prior to the introduction of contemporary adjunctive antiplatelet therapy, the use of stents during primary PCI was associated with an increased likelihood of impaired epicardial blood flow.22,25
Recently, the severity of thrombus burden in the culprit coronary arteries has proved to be an independent predictor of adverse cardiac clinical events.26 As a result, there has been increasing interest in the concept of clot burden reduction by mechanical devices to improve outcomes in patients undergoing PCI for occlusive thrombi. The recently published Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study (TAPAS) suggested that the use of thrombectomy devices in STEMI led to better indices of microvascular perfusion, which translated into improvements in clinical outcomes.27,28 However, many randomized trials of thrombectomy and distal protection devices during primary PCI have provided conflicting results without definitive evidence supporting their efficacy.29,30
In summary, currently available strategies are, at best, modestly effective in the prevention of distal embolization and microvascular dysfunction, but they do not reduce infarct size or mortality following PCI in patients with ACS in whom there is a high thrombus burden, highlighting the need to develop alternative strategies.
Intracoronary drug delivery. A relatively simple adjunctive strategy that may have therapeutic potential during PCI in thrombotic lesions is IC delivery of antithrombotic drugs. Though this approach has been used empirically in the past and still continues to be used in cardiac catheterization laboratories around the world, it has never been evaluated in a large-scale randomized study. There is increasing evidence to suggest that local delivery of GP IIb/IIIa receptor antagonists and fibrinolytic agents directly into the coronary circulation during PCI in patients with ACS may improve microvascular function and clinical outcomes. The rationale for this approach is the ability to achieve a very high concentration of the drugs at the site of the thrombus without significantly increasing the risk of bleeding.
The drug concentration after IC administration depends on coronary blood flow. It has been estimated that the concentration may be as much as 280-fold greater when compared to IV delivery, depending on inflow and washout of blood.31 Thus, a high concentration of antithrombotic agents at the site of a thrombotic lesion may facilitate the diffusion of the drug into the acute thrombus, with the potential of promoting clot dissolution in the epicardial and microvessels. Moreover, a high local concentration leads to increased receptor occupancy in the case of GP IIb/IIIa inhibitors.32 As a general rule, antithrombotic therapy for patients requiring PCI has consistently been accompanied by an increased risk of bleeding.33,34 Treatments used in current practice have been shown to reduce ischemic complications with an acceptable risk of bleeding, resulting in a net benefit. However, recent trials have demonstrated that efforts to further increase antithrombotic potency over and above contemporary therapies can lead to an increased risk of bleeding. Bleeding is independently associated with worse outcomes following PCI. In this regard, IC drug delivery has the potential to increase efficacy without a greater risk of bleeding. Indeed, it may be possible to combine potent antithrombotic drugs such as GP IIb/IIIa inhibitors and fibrinolytics, which, if given systemically, are known to increase the risk of major and minor bleeding, especially in high-risk patients such as the elderly.35,36 Thus, the ability to deliver a high drug concentration locally while maintaining a low systemic level is an attractive strategy.37
GP IIb/IIIa receptor inhibitors. Abciximab inhibits platelet aggregation, and in the presence of fresh thrombus, dissipates aggregates of platelets. It also inhibits platelet deposition on the thrombus, platelet-induced thrombin generation and diminishes the stability of clot structure, making it more susceptible to spontaneous, as well as pharmacological, fibrinolysis.38–42 In addition, abciximab appears to have anti-inflammatory effects through non-IIb/IIIa receptor-related properties. Since these properties exhibit a dose-response relationship, it has been speculated that IC administration may potentiate the putative anti-inflammatory actions and has the potential for improving microvascular function, reperfusion injury and clinical outcomes.43
The original evidence supporting the clinical use of IC administration of abciximab stems from early case reports describing complete dissolution of occlusive coronary thrombus with marked improvement in epicardial blood flow.44,45 More recently, several studies with small sample sizes have investigated the outcomes with IC delivery of abciximab and are summarized in Table 1. Wohrle and colleagues conducted the largest study to date involving 403 consecutive patients with acute MI or unstable angina. All patients received a 20 mg bolus of abciximab, which was administered either IV (n = 109) or IC (n = 294), followed by a 12-hour infusion (10 mg). In a retrospective analysis, the incidence of death, MI or urgent revascularization at 30 days was significantly lower in the patients treated with the IC bolus (10.2% vs. 20.2%; p 5 times the upper limit of normal) seen in the IV group (51%) compared with the IC group (26%) (p Conclusions
Percutaneous revascularization in thrombotic lesions remains a challenging prospect. Furthermore, strategies to prevent microcirculatory dysfunction in this subset of patients remain illusive. IV administration of currently available GP IIb/IIIa inhibitors has resulted in modest improvements in outcomes. Newer antithrombotic regimens, including direct thrombin inhibitors like bivalirudin, show some promise in the setting of acute coronary events. In the absence of any definitive strategy, current practice for treating lesions with angiographically detectable thrombus is variable and involves a combination of pharmacological and mechanical measures.
With regard to IC administration of antithrombotic agents, current evidence suggests that it is safe and feasible. The ease with which the drugs can be delivered through the guide or infusion catheters makes it an attractive concept. However, despite the promise shown by the predominantly small-scale, nonrandomized preliminary studies of improvement in surrogate endpoints of ischemia, there is insufficient evidence to change current practice. The results of the Leipzig study are very encouraging, and we believe that adjunctive IC delivery of antithrombotic drugs for thrombotic lesions deserves further evaluation in larger clinical trials with the goal of assessing definitive clinical endpoints. In addition, these trials would need to address unanswered questions such as whether a combination of antithrombotic drugs is superior to a single agent, the timing of delivery (before versus after PCI), and the optimal site of delivery (proximal versus distal to the lesion). Until proven otherwise, this strategy holds the promise of improving outcomes without significant additional risk or cost, a prospect that is infrequently encountered in the practice of medicine.
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