Rationale for low–molecular weight heparin in coronary stenting

Rationale for low-molecular weight heparin in coronary stenting James P. Zidar, MD D u r h a m , N o r t h Carolina

Stents have been as revolutionary for the practice of coronary revascularization in recent years as was the coronary angioplasty balloon 15 years ago, but they have also been associated with a high rate of stent thrombosis. The Enoxaparin and Ticlopidine After Elective Stenting (ENTICES) trial is designed to determine the impact of a reduced anticoagulation regimen on clinical outcomes after stent deployment. Patients are randomly assigned 2:1 to enoxaparin-ticlopidine-aspirin versus the conventional warfarin regimen, and surrogate markers of platelet activation and thrombin activity are measured after 3 days. Three factors underpin ENTICES: (1) a desire to eliminate stent thrombosis, (2) a desire to reduce length of stay after stent placement by avoiding the prolonged hospitalization required with the five-drug regimen of heparin, aspirin, dipyridamole, dextran, and warfarin, and (3} a desire to reduce the bleeding complicatians associated with the intense anticoagulation typically used in patients receiving stents. Patients are enrolled at seven sites in the United States and include patients with recent infarctions, restenotic lesions, and lesions as large as 30 rnm in length. Other trials have also addressed issues concerning anticoagulation in patients undergoing stenting. The Stent Antithrombotic Regimen Study (STARS) trial compared aspirin, aspirin plus ticlopidine, and aspirin plus warfarin in 1650 patients receiving stents. The Aspirin/Ticlopidine vs Low-Molecular Weighl Heparin/Aspirin/Ticlopidine High-Risk Stent Trial (ATLAST) is comparing aspirin plus ticlopidine with enoxaparin, aspirin, and ticlopidine in a group of patients at high risk undergoing stenting. The Intracoronary Stenting and Antithrombotic Regimen (ISAR) trial, a trial of ticlopidine, aspirin, and 12 hours of postprocedural heparin versus phenocoumaron on and aspirin after stenting in 517 patients, found a significantly lower incidence of the combined end point of death, myocardial infarction, bypass surgery, or repeated percutaneous transluminal angioplasty in the patients who received antiplatelet therapy, but the' patients enrolled were not representative of the usual population undergoing stenting. New trials of stents and their sequelae should include low-molecular weight heparins and should gather cost and outcome data to satisfy capitated systems and managed care. Innovative stent designs may also permit changes in antithrombotic regimens. (Am Heart J 1997;134:$81-$87)

Since the introduction of the coronary angioplasty balloon, no single technology has affected the clinical practice of coronary revascularization more than have coronary stents. Intracoronary stents have been shown to reduce abrupt closure, postinterventional urgent revascularization, target-vessel revascularization, and restenosis. 1,2 Stents of diverse designs have been proposed as intraluminal scaffolds to resist elastic recoil and "tack up" luminal dissections. The improvement in acute angiographic success of a well-deployed Palmaz-Schatz stent (Johnson & Johnson Interventional Systems, Warren, N.J.) with respect to conventional balloon angioplasty has led to an explosion in

From the Division of Cardiology, Department af Medicine, Duke University Medical Center. Dr. Zidar receives research funding from Rh6ne-PouleneRarer Pharmaceuticals.

Reprint requests: James P. Zidar, M.D., Assistant Professor of Medicine, Duke University Medical Center, Box 3290, Durham, NC 27710. Copyright © 1997 by Mosby- Year Baak, Inc, 0002-9703/97/$5.00 + 0 4/0/84738

the use Of stents around the world. More than 200,000 stents were implanted in 1995. The balance between specific anticoagulation regimens and stent thrombosis has changed dramatically in the last 2 years. When the first stents were deployed in patients a decade ago, there were no guidelines for treatment after stenting. The initial experience with the Wallstent (Schneider [USA], Inc., Plymouth, Minn.) resulted in a stent thrombosis rate of 18%, despite an aggressive anticoagulation regimen of heparin, dextran, aspirin, warfarin, sulfinpyrazone, and dipyridamole. 3 The early clinical experience with the Palmaz-Schatz stent had a similar 18% early occlusion rate, reinforcing the concern that coronary stents were highly thrombogenic. 4 This mentality prevailed within the interventional cardiology community until early 1994, when Columbo et al. 5 challenged this assumption in an investigation with intravascular ultrasonography. They postulated that stent thrombosis resulted from inadequate stent deployment and was less likely to be caused by the intrinsic thrombogenic nature of the stents.

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ENTICES trial design Many of the original antithrombotic regimens were recommended in the absence of strong comparative data. Nonetheless, a large body of nonrandomized data with reduced anticoagulation regimens has been gathered from Europe and some sites in the United States.6-8 These issues led to the design of a trial initiated at Duke University in early 1995. In an effort to further understand the impact of a reduced anticoagulation regimen on clinical outcomes, we enrolled a group of patients in the Enoxaparin and Ticlopidine After Elective Stenting (ENTICES) trial. The protocol coupled clinical outcomes with surrogate markers of thrombin activity and platelet activation in patients receiving elective Palmaz-Schatz stents for de novo and restenotic indications. Patients were randomly assigned in a 2:1 fashion to receive either ticlopidine, subcutaneous enoxaparin, and aspirin or conventional warfarin. The rationale for the ENTICES trial was partially driven by the high cost of stenting for elective use, involving a prolonged hospital stay for the five-drug regimen of heparin, aspirin, dipyridamole, dextran, and warfarin recommended in the package insert prepared by the U.S. Food and Drug Administration (FDA). New strategies that reduce length of stay are critical to the long-term acceptance of the stent as a routine therapy, especially in this country, with its growing emphasis on minimizing cost. The coupling of subcutaneous low-molecular weight heparin (LMWH) with ticlopidine allowed a safe anticoagulation regimen as we changed our clinical practice. A second motivation for this new trial was the desire for less intense anticoagulation to avoid the excessive vascular and bleeding complications in the stent groups of the Stent Restenosis Study (STRESS, 8%) and Benestent (9.7%) trials. We believed that combining aggressive antiplatelet agents but less anticoagulation with stenting would further reduce the need for repeated intervention and target-site revascularization. Before performing the ENTICES trial, we postulated that patients might have stent thrombosis at a higher rate with warfarin than with an antiplatelet regimen of aspirin, ticlopidine, and LMWH because depletion of proteins C and S would leave patients in a relatively hypercoagulable state during the 3- to 5-day period after stent implantation when thrombosis is likely to occur. We tested this hypothesis in a porcine coronary thrombosis model. 9 A group of five animals placed on a regimen of warfarin and aspirin for 3 days before stenting were compared with five animals treated with ticlo-

pidine and aspirin for 3 days before stenting. Each animal received two coronary stents (10 stents per group). Baseline angiograms were performed with on-line quantitative coronary angiography. All animals received intravenous heparin. Their platelets were radiolabeled with indium 111 one hour before implantation of 7 mm Johnson & Johnson slotted-tube stents. All stents were deployed at high pressure (>14 atm), and the animals were killed at 24 hours. The hearts were perfusion fixed, and the arterial segments were removed and placed under a gamma camera. All baseline laboratory, clinical, and angiographic variables were similar between the two groups of animals, including reference lumen, minimal luminal diameter before and after deployment, balloon size, maximum inflation pressure, stent-artery ratio, histologic analysis scoring of strut injury, maximum injury score, and percentage of medial disruption. The only difference was the baseline prothrombin time. The animals in the warfarin group had a prothrombin time of 16.5 seconds, whereas those on the ticlopidine regimen had a prothrombin time of 13.1 seconds (p = 0.003). We also noted an interesting difference, by gamma counting, in the number of platelets per square centimeter deposited on the stent surface. In the stented vessels treated with ticlopidine and aspirin, there were 1.74 -+ 0.45 x 108 platelets/cm 2, a marked reduction in the platelet deposition on the surface of the stents from the 3.69 + 1.16 x 108 platelets/cm 2 in the animals treated with warfarin and aspirin (p = 0.007). This study demonstrated a twofold increase in the potential thrombus burden with the combination of warfarin and aspirin versus the combination of ticlopidine and aspirin. Because the porcine model had previously been used as a surrogate for human coronary thrombosis, these differences in outcomes raised the question of whether the same effect would be present with the human coagulation system. While these animal studies were underway, ticlopidine was introduced to the European clinical community with great promise for coronary stenting. 1° Its antiplatelet effects are diverse and include the inhibition of adenosine diphosphate-induced platelet-fibrinogen binding and platelet aggregation. Bleeding time is prolonged. There is a delay in the effect of this agent, which does not achieve a steady state for more than 6 days. Unfortunately, ticlopidine carries with it an array of unpleasant side effects. The most common complications have been rashes and gastrointestinal disturbances such as dyspepsia, nausea, and diarrhea. However, the

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Timeline Eligible patients randomized prior to elective stent placement

* Baseline

Aspirin, Ticlopidine, LMWH (wgt adjusted) subq 10 days [80 patients]

'Conventional anticoagulation regimen [40 patients]

Ticlopidine 250 rag. bid x 30 days

Warfarin to INR 2.0 x 30 days

* Drawn at sheath

pull * Drawn at day 3 *Drawn at day 10

*Day 30

30-day clinical outcome

*Six months

6-month clinical outcome

*Lab values obtained: TAT, FPA, F1.2,d-dimer

ENTICES trial design. TAT, Thrombin-antithrombin complex; FPA, fibrinopeptide A; INR, International normalized ratio.

most worrisome complications are hematologic, with neutropenia and agranulocytosis appearing in 1% to 2% of patients. At least 10 deaths attributed to ticlopidine have been reported to the FDA. They have usually been immune mediated (aplastic anemia, idiopathic thrombocytopenic purpura, and pancytopenia) and have occurred at least 3 weeks after drug initiation (Fredd SB, personal communication, February 1996). The other agent we were interested in testing was enoxaparin (Lovenox), a LMWH. Enoxaparin is a fractionated heparin that allows subcutaneous injection with a high bioavailability. LMWHs bind less avidly to plasma proteins and endothelial cells and thus have increased bioavailability and duration of action. The complexes formed between antithrombin III and the LMWHs have weaker activity against thrombin than does standard heparin because of the saccharide chain-

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length dependence of this reaction. On the other hand, inhibition of factor Xa requires only a pentasaccharide subunit. So, unlike standard heparin, which has a 1:1 anti-Xa to antithrombin effect, the LMWHs generally have ratios between 2:1 and 4:1. Because of their smaller size, the LMWHs inactivate platelet-bound fac-tor Xa equally well and neutralize platelet factor 4 (which inhibits standard heparin). 11-13 Typically given as a weight-adjusted subcutaneous injection, LMWHs have a more predictable dose-response relationship that obviates the need for laboratory monitoring. Standard heparin is less than 65% bioactive when given subcutaneously, whereas LMWH has a bioavailability approaching 95%. The drug is relatively inexpensive, can be given on an outpatient basis, and is available in the United States for deep venous thrombosis prophylaxis with hip and knee surgery. In a

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meta-analysis of nine randomized trials from 1984 to 1994, Lensing et al. 14 compared adiusted-dose intravenous heparin with a fixed dose of subcutaneous LMWH in the initial treatment of deep vein thrombosis. In a cohort of more than 1000 patients, they noted a 53% reduction in recurrent venous thromboembolism, a 71% reduction in major bleeding, and a 45% reduction in mortality for the LM~VH group. Subcutaneous enoxaparin thus appeared to be a promising agent to evaluate in combination with ticlopidine. Since the ENTICES Trial was designed in late 1994, the understanding of anticoagulation after stent implantation has changed markedly. ENTICES was a relatively aggressive trial at that time, but as the trial is completed, it appears conservative. We included seven sites in the United States and organized a trial that was generalizable to the interventional community, with Veterans Administration centers, community hospitals, and academic centers offering a diverse level of stent experience. The same contrast agent, ioxaglate, was used in all patients during the intervention to eliminate any confounding effect of contrast-induced changes in platelet activation. The trial design is outlined in Fig. 1. In an effort to stimulate enrollment, we randomly assigned patients 2:1 in favor of the new drug regimen. The prima W end point of the study was a 3-day surrogate of several hematologic markers. Our choice of markers was guided by pilot percutaneous transluminal angioplasty (PTCA) data from Khan et al. 15 on fibrinopeptide A, thrombin-antithrombin complex, and the fibrin fragments F1.2. Day 3 was chosen as the primary end point to coincide with both our animal model experience and the peak time for stent thrombosis in previous trials. Although this was a relatively small trial, secondary clinical end points included procedural success, in-hospital complications, and a 30-day composite end point of stent thrombosis, death, myocardial infarction, urgent revascularization, and stroke. In addition, a 6-month composite end point is being collected. In our effort to better understand the role of various clotting parameters within the coagulation cascade in patients with coronary stents, more than 2000 blood samples will be analyzed at a central hematology core laboratory. The clinical end points are secondary because of the small sample size. The stent procedure followed the conventional practice of high-pressure stent deployment, with or without intravascular ultrasonographic guidance. The ENTICES trial included a wider population than most previous stent trials because patients with restenotic

lesions, patients who had recently (>48 hours previously) had myocardial infarctions, and lesions as large as 30 mm in length (requiring as many as two stents) were not excluded. These criteria reflected an attempt to have the trial mimic the use of stents in clinical practice. The periprocedural activated clotting time was maintained at 300 to 350 seconds. All patients received high-pressure balloon inflations to at least 16 atm after stent deployment. The warfarin regimen was the standard FDA regimen of heparin, aspirin, dipyridamole, dextran, and warfarin. The enoxaparin-ticlopidine-aspirin arm required patients to stay ~mtil day 3 for blood work and education on subcutaneous injections of enoxaparin. For the first 60 such patients enrolled in the trial, the average length of stay was 4 days, versus 6 days in the warfarin group. Patients could have easily been discharged the day after stent deployment in the enoxaparin-ticlopidine group, but we remained conservative in this small pilot study.

Other trials of anticoagulation and stenting ENTICES is one of a series of trials attempting to assess issues concerning anticoagulation in the stent population. In the STARS trial, a group of patients w h o underwent optimal stenting received aspirin alone, aspirin and ticlopidine, or aspirin and warfarin. The trial enrolled more than 1900 patients to randomly assign 1650 patients with "optimal stent deployment" to one of the three regimens. Enoxaparin was used for a subgroup of patients who did not have ideal stent results, although there was no control group. The aspirin-tidopidine group had the lowest 30-day composite event rate (0.6% for death, Q-wave myocardial infarction, or urgent coronary a~-tery bypass grafting). The rate in the aspirin group was 3.5%, and that in the aspirin-warfarin group was 2.4%. These significant differences among the groups should produce a change in the FDA labeling for anticoagulation recommended for elective stenting with the Palmaz-Schatz stent. This larger trial should establish a baseline control population for any future stent study. The role of agents such as enoxaparin in elective stenting is still unknown, although it represents an attractive intermediate degree of anticoagulation as even less potent anticoagulation strategies are evaluated in concert with early discharge from the hospital. The optimal antithrombotic regimen in patients at high risk after deployment of intracoronary stents is

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unknown. Clinical syndromes associated with intracoronary thrombus and thrombus visualized anglographically increase the risk of acute ischemic complications after coronary intervention. 16-19 Although the theoretic risk of subacute thrombosis in intracoronary stenoses containing thrombus had inhibited the investigation of stent deployment in patients with acute myocardial infarction, several recent observational studies have demonstrated the feasibility of intracoronary stents in this setting. 2° 23 We hypothesize that the combination of enoxaparin, aspirin, and ticlopidine will reduce ischemic complications compared with aspirin and ticlopidine at 30 days after intracoronary stent placement in patients at high risk, as defined by clinical or angiographic criteria. This hypothesis will be tested in the Aspirin/Ticlopidine vs Low-Molecular Weight Heparin/Aspirin/Ticlopidine High-Risk Stent Trial (ATLAST), in which 2000 patients will be enrolled in a prospective, randomized, doubleblind, parallel-group, placebo-controlled study. The primary objective is to demonstrate that adding 14 days of subcutaneous enoxaparin to concomitant aspirin and oral ticlopidine therapy will reduce the incidence of clinical end points (composite of death, nonfatal myocardial infarction, and urgent revascularization) among patients at increased risk for stent thrombosis. Subacute thrombosis was the Achilles' heel of stenting in the initial trials but has been markedly reduced with high-pressure balloon inflations, the combination of aspirin and ticlopidine, and the avoidance of warfarin anticoagulation. 5-8 In the Intracoronary Stenting and Antithrombotic Regimen (ISAR) trial, 517 patients were randomly assigned to receive ticlopidine and aspirin or phenprocoumon and aspirin after successful stent implantation. 24 At 30 days, 1.6% of the patients assigned to antiplatelet therapy and 6.2% of the patients assigned to anticoagulant therapy reached the primary end point: the composite of cardiac death, myocardial infarction, bypass surgery, or repeated angioplasty. Assignment to the antiplatelet group also resulted in a 16% relative risk (95% confidence interval 0.06 to 0.36) in the combined clinical end point composed of primary cardiac events and noncardiac events (including death, stroke, hemorrhagic events, and peripheral vascular events). Although these results were dramatic, this trial enrolled patients with discrete single lesions who were not representative of the general population undergoing coronary intervention. The authors do not comment on the outcomes of the 110 patients in their hospital who had stents placed during

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the period of enrollment but were excluded from the protocol, which may explain the extremely low event rate in the antiplatelet group. Hall et al. 25 demonstrated the importance of both ticlopidine and aspirin after stent implantation. They randomly assigned 226 patients to receive aspirin alone or aspirin and ticlopidine for 5 days after intravascular ultrasonographically guided stent implantation. At 1 month, the stent thrombosis rate was 2.9'% in the aspirin-alone group and 0.8% in the aspirinticlopidine group (p = 0.2). The incidence of major clinical events (stent thrombosis, death, myocardial infarction, need for reintervention [coronary artery bypass grafting or PTCA], and significant medication side effects requiring termination) at 1 month was 0.8% in the aspirin-ticlopidine group and 3.9% in the: aspirin-alone group. These extremely low event rates at a single center may not be representative and need to be confirmed with a larger multicenter study. Remarkably, the ability of heparin to reduce ischemic complications after coronary intervention has not been subjected to a randomized trial. Information is largely limited to retrospective analyses documenting decreased abrupt closure and ischemic complications in patients who receive heparin to maintain a therapeutic activated clotting time during intervention. 26-36 The appropriate duration of heparin therapy after interven.tion is controversial. Activation of the coagulation sys,tern after the abrupt cessation of heparin therapy in patients with acute myocardial infarction after successful PTCA is a particular problem, as described by Granger et al. 37 In patients with unstable angina, the benefit of heparin therapy is attenuated by "heparin rebound" and reactivation of ischemia on its disconti~.uation. Th6roux et al. 38 reported reactivation of unsta-ble angina and myocardial infarction in 14 of 107 patients treated with heparin alone at a median of 9.5 hours after discontinuation of treatment. Logistic regression analysis revealed that therapy with heparin alone was the most important predictor of reactivation of the disease process. The promise of LMWHs to inhibit thrombosis while producing fewer bleeding complications and their favorable pharmacodynamics has stimulated their development and evaluation in clinical trials. Patients at high risk undergoing stenting appear to be an ideal group in which to test LMWHs because of the increased incidence of ischemic complJLcations shortly after stent deployment. All future stent trials designed to alter clinical practice should gather cost and outcome data, because capitated

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systems and managed care represent a growing segment of our practice. In highly-capitated areas, physicians have been innovative in ways to obtain reimbursement for outpatient medications such as enoxaparin by bundling them into the in-hospital stay costs covered through the managed care organization. The clinical evaluation of new stent designs remains on the distant horizon, with the heparin-coated stent from Johnson & Johnson as the first coated stent with some potential local drug effect to be available in the United States. These innovations may allow further alterations in the antithrombotic regimen necessary with stenting and warrant further scientific evaluation in randomized, prospective fashion.

References 1. Serruys PW, de jaegere P, Kiemeneij F, Macaya C, RutschW, Heyndrickx G, el el. A comparison of balloon-expandable-stenl implantation with balloon angioplasty in patients with coronary artery disease. N Engl j Med 1994;331:489-95. 2. Fischman DL, Leon MB, Bairn DS, Schotz RA, Savage MP, Penn I, et ak A randomized comparison of coronary-stenl placement and balloon ongioplasty in the lreatment of coronary artery disease. N Engl J Med 1994;331:496-501. 3. Serruys PW, Sllauss BH, Beatl KJ, Berlrand ME, PuelJ, Rickards AF, el al. Angiographic follow-up after placement of e selfiexpanding coronary artery s~ent.N Eng[ j Med 19911324:13-Z 4. Schatz RA, Bairn DS, Leon M, Ellis SG, GoJdberg S, Hirshfeld JW, et al. Clinical experience with the Palmaz-Schatz coronary stent: initial results of a multicenter study. Circulalion 1991 ;83:148-61. 5. Columbo A, Hall P, Nakamura S, Almagar Y, Maiello L, Martini G, et al. Intracoronary stenting without anlicoagulalion accomplished with intravascular ultrasound guidance. Circulation 1995191:1676-88. 6. Morice MC, Bourdonnec C, LefevreT, B[anchard D, Monassier JP, Lienhort Y, et al Coronary stenling wilhout coumadim phase llI [abstract]. Circulation 1994;90{suppl 4}:1125. Z Barragan P, SainsousJ, Silvestri M, Bouvier JL, Comet B, Sim~oni jB, et al. Ticlopidine and subcutaneous heparin as an alternative regimen following coronary stenting Cothet Cardiovasc Diogn 1994;32:]33-8. 8. Jordan C, Carvalho H, FaiadetJ, Cassagneau B, Robert G, Marco j. Reduction of subacute thrombosis tale after coronary stenting using a new anticoagulation protocol [abstract]. Circulation 1994;90(suppl 4):1 ]25. 9 Kruse KR, TanguayJF, Armstrong BA, Phillips HR, ZidarJP, Stack RS. Coumadin versus ticlopidine in an animal model of stent thrombosis: a comparative study [abstract]. Circu/alion 1995;92(supp[ 5):1485. 10. Serruys PW, Di Marie C. Who was thrombogenic: the stent or the doctor? Circulation 1995;91:1891-3. 11. B6guin S, Mardiguian J, Lindhout T, Hemker HC. The mode of action of low molecular weight heparin preparation (PK10169) and ~ o of its major components on thrombin generation in plasma. Thromb Haemost 1989161:30-4 12. Vairel EG, Bouty-Boye H, TouJemonde F, Doutremepuich C, Marsh NA, Gaffney PJ. Heparin and a low molecular weight fraction enhances thrombolysis and by this pathway exercises a protective effect against thrombosis Thromb Res 1983;30:219-24

13. Lane DA, Denton J, Flynn AM, Thunberg L, Lindahl U. Anticoagulant aciivities of heparin ohgosaccharides and their neutralization by platelet factor 4. Biochem J 19841218:725-32. 14. LensingAW, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with Cow-molecular-weightheparins: a metaanaly sis. Arch Intern Med 19951155:601-Z 15. Khan MM, Sepulveda J, Jeroudi Me, Levy GV, Schafer AI, Raizner AE, et ak Rebound increase in thrombin activity with associated decrease in antithrombin I11levels after PTCA [abstract] Circulation 1995192(suppl 1):/785. 16. Lincoff AM, Popma j j, Ellis SG, Hacker JA, Topoi EJ. Abrup~ vessel closure complicating coronary angioplasty: clinical, angiographic and therapeutic profile. J Am Call Cardio11992;19:926-35. 1Z Ellis SG, Roubin GS, King SB 3rd, Douglas jS Jr, Weintraub WS, Thomas RG, et al. Angiogrophic and clinical predictors of acute closure after native vessel corenary angioplasty. Circulation 1988;77:3729 18. Reeder GS, Bryant SC, Suman VJ, Holmes DR Jr. Intracoronory thrombus; still a risk factor for PTCA failure? Cathel Cardiovasc Diagn 1995;34:191-5. 19. Tenaglio AN, Fortin DF, Cahff RM, Frid DJ, Nelson CL, Gardner L, el ak Predicting the risk of abrupt vessel closure after angioplas~ in an individuar patient. J Am Corr Cardior 1994;24:]004 1]. 20. Rodriguez AE, Fernandez M, Santaera O, Larribau M, Bernardi % Castar~o H, et al. Coronary stenting in patients undergoing percuta neous transluminal coronary angioplasty during acute myocardial infarction. Am J Cardie11996;77:685-9. 21. Steinhubl SR, Moliterno Dj, Teirslein PS, Guarneri EM, Aguire FV, Ferguson JJ, et ok Stenting for acute myocardial infarction: the early United States mu[ticenter experience [abstract]. J Am Coil Cardiol 1996; 27: 279A. 22. Wong PHC, Wong CM. Introcoronary stenting in acute myocardial infarction. Cathet Cardiovasc Diogn 1994;33:39-45. 23. Walton AS, Oesterle SN, Yeung AC. Coronary artery stenting for acute closure complicating primary angioplasty for acute myocardial infarction Cathet Cardiovasc Diagn 1995134:142-6 24. Sch6mig A, Neumann FJ, Kastrati A, Sch0hlen H, Blasini R, Hadamitzky M, el el. A randomized comparison of antipJateJetand anticoagulant therapy after the placement of coronary-artery stents. N EngiJ Med 1996;334:10849. 25. Hall P, Nakamura S, Maiello L, Itoh A, Blengino S, Martini G, et al. A randomized comparison of combined ticlopidine and aspirin therapy versus aspirin therapy alone after successful intravascular ultrasoundguided stent implantation. Circulation 1996;93:215-22. 26. McGarry TF Jr, Gottlieb RS, Morganroth j, Zelenkofske SL, Kasparian H, Duca PR, el al. The relationship of anticoagulation level and camplicatfons after successful percutaneous/ransluminal coronary angioplasty. Am HeartJ 1992;123:1445-51. 2Z Dougher V KG, Marsh KC, Eddman SK, Gaos CM, Fergusonj J, Leachrnan DR Relationship be~een procedural activated dotting time and in-hospital post-PTCA outcome [abstract]. Circulation 1990;82(suppl 3):111189. 28. Rath B, Bennett DH. Monitoring the effect of heparin by measurement oF activoled clotting time during and after percutaneous transluminal coronary angioplasty Br Heart J 1990;63:18-21. 29. Vaitkus PT, Herrmann HC, Laskey WK. Management and immediate outcome of patients with intracoronary thrombus during percutaneous transluminal coronary angioplasty. Am Heart J 1992; 124:1 8.

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30. Gabhani G, De/igonul U, Kern Mj, Vandormael M Acute coronary occlusion occurring after successful percutaneous transluminal coronary angiopbsty: temporal relationship to discontinuation of anticoagulation. Am Heart J 1988;116:696-700. 31+ QgilbyJD, KopeJman HA, Klein LW, Agarwal jB. Adequate heparinization during PTCA: assessmentusing activated clotting times. Cathet Cardiovasc Diagn 1989;18:206-9. 32. Satler LF, Leon MB, Kent KM, Pichard AD. Strategies for acute occlusion after coronary angioplasty, j Am Coil Cardid 1992;19:936-8. 33. FergusonJJ, Daugherty KG, Gaos CM, Bush HS, Marsh KC, Leachrnan DR. Relation between procedural activated coagulation time and outcome after percutaneous transluminal coronary angioplash. J Am Coil Cardid 1994;23:1061-5. 34. Narins CR, Hillegass WB, Nelson CL, Tcheng JE, Harrington RA,

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36.

3Z

38.

Phillips H R, el a[. Relation between activated clotting time during angioplasty and abrupt closure. Circulation 1996;93:667-71. Mooney MR, MooneyjF, Goldenberg IF, Aimquist AK, Van Tassel RA. PercutaneoustransluminaJcoronary angioplasty in the setting of Parge intracoronary thrombi. Am j Cardial 1990;65:427-31. PopmaJj, Caller BS, Ohman EM, BittlJA, Weitz J, KunPzRE, et aL Antithrambotic therapy in patients undergoing coronary angiopPasty. Chest 1995;108(suppJ 4):486S-501 S. Granger CB, Miller JM, BovilJEG, Gruber A, Tracy RP, Krucoff MW, er al. Rebound increase in thrombin generation and activity after cessation of intravenous heparin in patients with acute coronary syndromes. Circubtion 1995;91:1929-35. Th6roux P,Waters D, LainJ, Juneau M, McCans J. Reactivation of unstable angina after the discontinuation of heparin. N Engl J Med 1992;327:141-5.