The End of Systemic Anticoagulation Therapy for Restenosis Prevention

Multiple in vitro and in vivo studies have suggested that interactions involving thrombosis, coagulation proteins, and the arterial wall may be important in neointimal tissue growth and restenosis.1 It has also been shown that vascular smooth muscle cell proliferation plays a major role in the genesis of restenosis after angioplasty or vascular injury. In addition to its anticoagulant effects, heparin has been widely reported to inhibit smooth muscle cell proliferation and migration, which is widely recognized as the most important mechanism of restenosis.2,3 In vitro experiments using cell culture and animal models have demonstrated that heparin may reduce intimal hyperplasia by 30–60% and that low molecular weight heparin (LMWH) is a more potent antiproliferative agent than unfractionated heparin (UFH), independent of its anticoagulant effects.4 Compared with UFH, LMWHs have reduced binding to plasma proteins and cells and longer plasma half-life. These properties are responsible for the more predictable dose-response relationship and sustained anticoagulant effects of LMWHs and led to a series of clinical studies inquiring possible applications of LMWHs in the cardiac catheterization laboratory, and especially in one of the hottest topics of interventional cardiology: prevention of restenosis.5 The effects of systemic heparin in intimal hyperplasia were reproducible in vitro but have been contradictory in vivo; intimal hyperplasia was reduced after balloon-induced injury in some animal models (rat carotid and porcine) but not in others (baboon).3,4 Studies in animal models indicating that LMWH suppresses neointimal proliferation after balloon angioplasty prompted clinical trials to evaluate the effect of LMWH on the rate of restenosis.4,6 There is only one prospective randomized trial in which the local delivery of a LMWH (10 mg enoxaparin before stenting) resulted in a reduction in restenosis after stent implantation in de novo coronary lesions.7 In this issue, Grassman et al. have approached the effectiveness and safety of the LMWH certoparin in preventing restenosis after coronary angioplasty. The study was a double-blind, placebo controlled, randomized trial with 2 study groups, conducted at 4 centers and included patients referred for elective balloon angioplasty. At the time of the procedure, patients were randomly assigned to treatment with twice-daily subcutaneous injections of certoparin or placebo for 3 months. Target lesion restenosis (late lumen loss), assessed by quantitative angiography, was the main outcome used to evaluate the efficacy of long-term certoparin administration, and no significant difference was found between certoparin and placebo. However, a lower binary restenosis rate was found with the certoparin group; this finding was attributed to the smaller reference vessel diameter in the LMWH group compared to placebo. The findings of this trial are consistent with several published reports using unfractionated heparin or various LMWHs for prolonged periods after angioplasty that failed to show any advantage over placebo. The LMWH restenosis trials are summarized in Table 1. The current study used certoparin 80 mg (8,000 anti-XaU) for three months, the second, more intense regimen among the tabulated trials. Systemic heparin delivery (as systemic administration of any pharmaceutical agent) has two important limitations: 1) the inability to rapidly achieve an adequate drug concentration within the arterial wall, and 2) extracardiac side effects limit needed increases in dosing. An alternative approach is to achieve the desired arterial wall levels by the intracoronary (local) delivery of pharmacologic agents as heparin.8 Local delivery of heparin into porcine carotid arteries reduced platelet deposition in the initial 12 hours after angioplasty-induced injury.4 However, this failed to translate in any reduction of restenosis in the Heparin Infusion Prior to Stenting (HIPS) trial (single infusion of 5,000 IU heparin intracoronary before the procedure).9 Intramural delivery of nadroparin with a micro-porous catheter after stent deployment was tested with similar results in the IntraMural infusion of low molecular weight heparin to Prevent REStenosis after Stent (IMPRESS) implantation trial.10 There are numerous potential explanations for these largely negative results regarding prevention of restenosis. First, it is unlikely that the heparins (both UFH and LMWH) actually limit neointimal tissue growth after balloon injury in humans. Second, in most of these studies, pretreatment and a higher dosing regimen were not employed due to bleeding considerations. Third, arterial narrowing after coronary intervention results from complex interactions including recoil, negative remodeling and neointimal tissue growth, and the contribution of these factors may vary among different patient subgroups treated with different drugs or devices. This is especially true in balloon angioplasty studies (such as the one by Grassman et al). With respect to local drug delivery, trauma to the arterial wall induced by various microporous catheters used, accompanied by high pressure inflation, may have resulted in less than optimal delivery of the various agents. Fourth, several studies were probably underpowered to show any improvement in restenosis rates. Discordant with the above findings is the recent POlish-American local LOvenox NIR Assessment (POLONIA) trial, which is the only prospective, randomized study that used a local delivery system and showed a favorable effect of enoxaparin in restenosis rates.7 This study sought to determine whether the intramural delivery of enoxaparin before stenting of de novo lesions decreases restenosis (angiographic late lumen loss). Of note, the delivery of enoxaparin in POLONIA was performed during predilation (before stent implantation) in order to improve intramural penetration of the highly concentrated drug at low pressure and to minimize arterial trauma, while other studies (i.e., IMPRESS) used different administration strategy. Nonetheless, POLONIA was a small-size study (n = 100) and its findings need confirmation by a larger trial. In addition, these effects may be attributed to unique antiproliferative properties of enoxaparin, which may not apply for unfractionated heparin or other low molecular weight heparins.6 One must take into account that LMWHs vary in chemical and ionic structure (sodium or calcium salts), release profile of tissue factor pathway inhibitor and anti-Xa/anti-IIa activity.4,11 Given these differences and variation in clinical effectiveness in other conditions such as acute coronary syndromes and venous thromboembolism we believe that these agents should not be considered as a uniform class of identical agents; rather, they have to be evaluated independently.4,5 In conclusion, systemic administration of any type of heparin has not prevented restenosis in any study. It is time that we move on and focus on other more promising methods to tackle the restenosis problem.

1. Skaletz-Rorowski A, Schmidt A, Breithardt G, et al. Heparin-induced overexpression of basic fibroblast growth factor, basic fibroblast growth factor receptor, and cell-associated proteoheparin sulfate in cultured coronary smooth muscle cells. Arterioscler Thromb Vasc Biol 1996;16:1063–1069. 2. Hammerle H, Betz E, Herr D. Human endothelial cells are stimulated and vascular smooth muscle cells are inhibited in their proliferation and migration by heparins. Vasa J Vasc Dis 1991;20:207–215. 3. Hirsh J, Anand SS, Halperin JL, and Valentin Fuster Guide to Anticoagulant Therapy. Heparin: A statement for healthcare professionals from the American Heart Association. Circulation 2001;103:2994–3018. 4. Antman EM. The search for replacements for unfractionated heparin. Circulation 2001;103:2310–2314. 5. Wilensky RL, March KL, Gradus-Pizlo I, et al. Vascular injury, repair, and restenosis after percutaneous transluminal angioplasty in the atherosclerotic rabbit. Circulation 1995;92:2995–3005. 6. Gikakis N, Rao AK, Miyamoto S Jr., et al. Enoxaparin suppresses thrombin formation and activity during cardiopulmonary bypass in baboons. J Thorac Cardiovasc Surg 1998;116:1043–1051. 7. Kiesz RS, Buszman P, Martin JL, et al. Local delivery of enoxaparin to decrease restenosis after stenting: Results of initial multicenter trial: Polish-American Local Lovenox NIR Assessment study (The POLONIA study). Circulation 2001;103:26–31. 8. Pavlides GS, Barath P, Maginas A, et al. Intramural drug delivery by direct injection within the arterial wall: First clinical experience with a novel intracoronary delivery-infiltrator system. Cathet Cardiovasc Diagn 1997;41:287–292. 9. Wilensky R, Tanguay J-F, Ito S, et al. The Heparin Infusion Prior to Stenting (HIPS) Trial: Procedural, in-hospital, 30-day, and six-month clinical, angiographic and IVUS results. J Am Coll Cardiol 1998;31:457A. 10. Meneveau N, Schiele F, Grollier G. Local delivery of nadroparin for the prevention of neointimal hyperplasia following stent implantation: Results of the IMPRESS trial. A multicentre, randomized, clinical, angiographic and intravascular ultrasound study. Eur Heart J 2000;21:1767–1775. 11. Alban S, Gastpar R. Plasma levels of total and free tissue factor pathway inhibitor (TFPI) as individual pharmacological parameters of various heparins. Thromb Haemost 2001;85:824–829. 12. Faxon DP, Spiro TE, Minor S, et al. Low-molecular-weight heparin in prevention of restenosis after angioplasty. Results of enoxaparin restenosis (ERA) trial. Circulation 1994;90:908–914. 13. Karsch KR, Preisack ML, Baildon R, et al. Low-molecular-weight heparin (reviparin) in percutaneous transluminal coronary angioplasty. Results of a randomised, double-blind, unfractionated heparin and placebo-controlled, multicenter trial (REDUCE trial). J Am Coll Cardiol 1996;28:1437–1443. 14. Cairns JA, Gill J, Morton B, et al. Fish oils and low-molecular-weight heparin for the reduction of restenosis after percutaneous transluminal coronary angioplasty: The EMPAR study. Circulation 1996;94:1553–1560. 15. Lablanche JM, McFadden EP, Meneveau N, et al. Effect of nadroparin, low-molecular-weight heparin, on clinical and angiographic restenosis after coronary balloon angioplasty: The FACT (Fraxiparine Angioplastie Coronaire Transluminale) study. Circulation 1997;96:3396–3402. 16. Gimple LW, Herrmann HC, Winniford M, et al. Usefulness of subcutaneous low molecular weight heparin (ardeparin) for reduction of restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol 1999;83:1524–1529.