Preventing Subacute Stent Thrombosis — Is There a Role for Heparin-Coated Stents?

With the first implants of stents in coronary arteries, the promise of predictable, stable, catheter-based revascularization became a reality. However, as with many new therapies, the treatment can give rise to new disorders. In the earliest series of patients treated with the self-expanding Wallstent, 18% suffered thrombotic occlusion of the newly implanted stent. Importantly, this high rate of subacute stent thrombosis was a major contributor to an 8% one-year mortality rate.1 Prevention of this devastating complication became the impetus for using complex adjunctive pharmotherapies. The earliest regimens combined several relatively weak antiplatelet agents such as aspirin, dipyridamole and dextran. Despite these medications, the incidence of stent thrombosis remained unacceptably high (16–20%).1,2 The addition of uninterrupted anticoagulation with heparin and warfarin reduced the incidence to 3%.2 However, the reduction in thrombotic events came with an expensive price tag, prolonged hospitalization and high rates (~14%) of hemorrhagic complications.3 As the wave of "stentmania" propagated over the interventional landscape in the mid 1990s, interventional cardiologists were forced into a Hobson’s Choice between hemorrhagic or thrombotic complications. A major breakthrough in the prevention of stent thrombosis followed the seminal observations of Colombo, who documented with intravascular ultrasound that the majority of stents were incompletely expanded.4 Utilizing a combination of high-pressure post-dilatation accompanied by dual antiplatelet therapy with aspirin and the thienopyridine derivative ticlopidine, the incidence of stent thrombosis was reduced to less than 1%. This strategy was evaluated prospectively in the STARS trial in which patients who underwent successful stenting were randomized to either aspirin alone, aspirin and warfarin, or aspirin and ticlopidine. The combination of aspirin and ticlopidine was clearly superior to the other two regimens with a stent thrombosis rate of only 0.5% (compared to 2.7% for aspirin and warfarin, and 3.6% for aspirin alone).5 The superiority of a dual antiplatelet regimen combining aspirin and ticlopidine was corroborated in several other randomized trials, and rapidly became standard of care following stenting. The impact of this transition from a warfarin to a thienopyridine-based regimen cannot be overstated. Duration of hospitalization and rates of vascular complications fell dramatically, removing two significant obstacles to the use of stents as the default catheter-based treatment of coronary artery disease. Nevertheless, dual antiplatelet therapy has not been a panacea for all thrombotic events related to stent placement. Ticlopidine is associated with neutropenia in 1.5% of patients and life-threatening thrombotic thrombocytopenia purpura in a small number of patients.6 Consequently, most interventionalists have replaced ticlopidine with clopidogrel, which appears to offer similar efficacy but significantly less side effects.7 Still, the addition of a second antiplatelet agent to aspirin comes at a price. Clopidogrel is expensive and increases the risk of bleeding compared to aspirin alone, especially if the patient must undergo surgery within 5–7 days of drug administration. Most importantly, although the STARS trial documented a 0.5% incidence of subacute stent thrombosis with dual antiplatelet therapy, experience in the "real world" suggests that the true incidence of subacute stent thrombosis may be significantly higher.8 Unfortunately, systemic antiplatelet and anticoagulant therapy, if efficacious, must incur incremental risk of hemorrhage. Stent placement followed by aspirin alone, if accompanied by subacute thrombosis rates below one percent, clearly would reduce the morbidity and mortality of stenting. Ideally, local therapy would alter the thrombotic milieu in the absence of a systemic effect. That stents are ideally suited for in situ therapy is obvious. Stent-based local pharmacotherapy can be accomplished by either alteration in surface properties or by drug elution. Corrosion-resistant metal alloys such as stainless steel or nitinol are inherently thrombogenic. Soon after deployment in the vasculature, platelets and fibrin adhere rapidly to these metal surfaces. Approaches to reducing thrombus deposition on stent struts have included coating the metallic struts with thromboresistant materials such as silicum carbide and phosphoryl choline. The heparin-coated BX Velocity stent (Hepacoat, Cordis Corporation, Miami Lakes, Florida) represents another attempt at rendering a stainless steel surface relatively thromboresistant. It is important to remember that the Hepacoat stent does not elute heparin. Instead, heparin is covalently bonded to a polymer using a process termed “endpoint attachment”. This exposes a pentasaccharide moiety in the heparin molecule that binds to antithrombin III, leading to its activation. Thus, the stent serves as an in situ catalyst allowing repetitive activation of antithrombin III. The two most important questions relating to the efficacy of heparin-coated stents are can the stents be placed with a low incidence of subacute thrombosis in patients treated with aspirin alone, and are they associated with lower risk of thrombosis compared to bare metal stents in the presence of dual antiplatelet therapy? Since the absolute risk of stent thrombosis is low, any prospective, randomized study would require a large sample size to demonstrate a statistically meaningful difference. As so often happens in medicine, clinical decisions must be made in the absence of the "gold standard" of blinded, placebo-controlled trials. Let us address the second scenario first. Are there circumstantial data to support the superiority of heparin-coated stents compared to bare metal stents? Three studies, Benestent II, TOSCA and PAMI-Stent, have treated a large number of patients with heparin-coated stents. It is important to remember that none of these studies compared heparin-coated to non-coated stents.9–11 Nevertheless, if the data are pooled from these studies, 1,369 patients were treated with heparin-coated stents. The rate of subacute stent thrombosis was 0.4% overall, 0.7% for stents placed for acute myocardial infarction, and only 0.1% for stents placed for indications other than acute myocardial infarction. As is often the criticism of clinical trials, perhaps these low complications rate reflect the controlled environment of clinical research performed by a small number of operators, rather than a "real world" experience? The HEPANET Study addressed this question.12 HEPANET is an international, multicenter registry using the internet to compare the rates of subacute thromboses in Hepacoat stents compared to non-heparin coated Bx Velocity stents (Cordis Corporation). Data from 2,139 patients were collected. The incidence of subacute thrombosis was 50% lower in patients treated with heparin-coated stents (0.5% vs. 1.0%), with the most profound effect observed in patients treated at European centers (0% vs. 1.3%; p = 0.04). In aggregate, these studies suggest that stents with heparin covalently bound to their surfaces may be more resistant to thrombotic occlusion than bare metal stents. In this issue of the Journal of Invasive Cardiology, Ruygrok and colleagues provide data from the PHARAO Study in which See Ruygrok et al. on pages 439–441 a single Hepacoat stent was deployed in relatively small vessels (mean reference vessel diameter = 2.44 mm) in 122 patients treated with only aspirin.13 Within the first month, no major adverse cardiac events were reported suggesting that the combination of a heparin-coated stent and aspirin alone was sufficient to avoid thrombotic occlusions. The findings of the PHARAO study are in accord with the HOPE registry in which 202 patients were treated with heparin-coated stents and aspirin alone.14 The incidence of subacute stent thrombosis was only 1%. Based on these two studies, it is tempting to conclude that clopidogrel and ticlopidine should join dextran, dipyridamole, and warfarin on the "scrap pile" of drugs that no longer have a role in contemporary stenting. However, several caveats are in order. Even though no cases of subacute thrombosis were observed in PHARAO, the upper boundary for the 95% confidence interval is 3%. In addition, in both PHARAO and HOPE, lesions at highest risk for stent thrombosis such as those containing thrombus and vessels with slow flow, were excluded. Thus, the generalizability of these findings to many lesions treated in contemporary practice, e.g., vessels

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