Antithrombotic Therapy During PCI 177 death, reinfarction, or urgent target vessel revascularization at 30 days in patients treated with abciximab (4.9%) versus placebo (10.3%) (22). There was no differ- ence in 6-month restenosis between the two groups (22). To evaluate the effect of abciximab in low-risk patients undergoing PCI, the Evaluation of PTCA to Improve Long-Term Outcome by abciximab GP IIb- IIIa blockade (EPILOG) trial randomly assigned 2792 patients who were treated with aspirin to standard-dose, weight-adjusted (100 U/kg bolus) heparin and pla- cebo, standard-dose, weight-adjusted heparin and abciximab, or low-dose, weight-adjusted (70 U/kg bolus) heparin. The 30-day composite event rate was significantly lower (p Ͻ 0.001) in patients treated with abciximab and low-dose (5.2%) or standard-dose (5.4%) heparin than in patients treated with standard- dose heparin and placebo (11.7%) (23). Bleeding complications were lowest in patients treated with abciximab and low-dose, weight-adjusted heparin. The effect of GPIIb-IIIa inhibitors has been more variable in patients under- going saphenous vein graft intervention. While one study suggested a beneficial effect with abciximab in patients undergoing SVG angioplasty (24), a larger study failed to demonstrate a convincing reduction in these patients at high risk for microembolization (25). Bailout abciximab is often given during or just after PCI for the presence of residual dissection, thrombus, or suboptimal results (26), although its value has not been demonstrated in prospective studies. The EPISTENT trial randomly assigned 2399 patients with ischemic CAD to stenting plus placebo, stenting plus abciximab, or balloon PTCA plus abcixi- mab (27) and found that the primary 30-day endpoint, a combination of death, MI, or need for urgent revascularization, occurred in 10.8% of patients in the stent plus placebo group, 5.3% of patients in the stent plus abciximab group (hazard ratio 0.48; p Ͻ 0.001), and 6.9% of patients in the balloon plus abciximab group (0.63; p ϭ 0.007) (27). The primary benefit of abciximab was in the reduc- tion of death and large (CPK-MB Ͼ 5 ϫ normal) MI, which occurred in 7.8% of patients in the placebo group versus 3.0% of patients assigned to stent plus abciximab group (p Ͻ 0.001) and 4.7% of patients treated with balloon PTCA plus abciximab (p ϭ 0.01) (27). No differences in bleeding complications were found among the groups (27). Other GP IIb-IIIa inhibitors have also been used in patients undergoing PCI. The IMPACT-II trial evaluated the effect of bolus and infusion eptifibatide on 30-day clinical events in patients undergoing PCI. A total of 4010 patients undergoing PCI were assigned to placebo, eptifibatide bolus (135 µg/kg) fol- lowed by a low-dose eptifibatide infusion (0.5 µg/kg/min for 20 to 24 h) or the same eptifibatide bolus and higher dose infusion (0.75 µg/kg/min for 20 to 24 h) (29). The primary endpoint, a 30-day composite occurrence of death, MI, un- planned CABG or repeat PCI, or coronary stenting for abrupt closure, occurred in 11.4% patients in the placebo group compared with 9.2% in the 135/0.5 eptifi- batide group (p ϭ 0.063) and 9.9% in the eptifibatide 135/0.75 group ( p ϭ 178 Popma and Askari 0.22) (29). Using a treatment-received analysis, the eptifibatide 135/0.5 regimen produced a significant reduction in the composite endpoint (9.1% vs. 11.6% in placebo-treated patients; p ϭ 0.035), but the eptifibatide 135/0.75 regimen pro- duced a less substantial reduction (10.0% vs. 11.6% in placebo-treated patients; p ϭ 0.18). There were no differences in major bleeding or transfusion rates among the three groups. It is now understood that the eptifibatide dose used in the IMPACT-II trial was insufficient to provide adequate platelet inhibition during PCI. The recently completed, randomized ESPRIT trial compared a 180-µg/kg double bolus given 10 min apart of eptifibatide followed by a 2.0-µg/kg/min infusion with placebo in lower risk patients undergoing stent implantation. Preliminary results from this trial show a substantial benefit of eptifibatide compared with placebo in patients undergoing stent implantation (J. Tcheng, personal communications). Tirofiban is a nonpeptidyl, tyrosine derivative that was evaluated after PCI in the Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis (RESTORE) trial, a randomized, double-blind, placebo-controlled study involv- ing 2139 patients undergoing PCI who presented within 72 h of an acute coronary syndrome (30). After treatment with aspirin and heparin, patients were randomly assigned to tirofiban bolus (10 µg/kg over 3 min) ϩ infusion (0.15 µg/kg/min), or to placebo bolus ϩ infusion for 36 h after PCI. There was a 16% reduction in the primary 30-day composite endpoint rate associated with tirofiban treatment (p ϭ 0.160), although there was a 38% relative reduction in the composite end- point at 48 h ( p Ͻ 0.005) and a 27% relative reduction at 7 days (p ϭ 0.022) (30). A 24% reduction was found when only urgent or emergency balloon angio- plasty or CABG was included in the composite endpoint (30-day event rate: 10.5% for the placebo group and 8.0% for the tirofiban group; p ϭ 0.052). Al- though major bleeding tended to be higher in tirofiban-treated patients (5.3 vs. 3.7% in the placebo-treated patients; p ϭ 0.096), there was no difference in bleed- ing events using the TIMI criteria (31) for major bleeding (30) in those treated with tirofiban. C. Effect of Antiplatelet on the Prevention of Restenosis Studies evaluating the effect of aspirin on restenosis have produced conflicting results, potentially attributable to the varied dosage and duration of aspirin ther- apy (1,32–34). Although the majority of these studies have shown little, if any, sustained effect of aspirin on restenosis prevention, long-term aspirin (Ͼ80 mg daily) is recommended after PCI for secondary prevention of cardiac events (35). Ketanserin, prostacyclin, platelet thromboxane A 2 and serotonin receptor antago- nists, respectively, have also been tried without success (36–40). As platelet aggregation during PCI may occur as a result of GP IIb-IIIa activation by a number of agonists, inhibition of a single agonist for the preven- Antithrombotic Therapy During PCI 179 tion of restenosis may be problematic. Final common pathway GP IIb-IIIa platelet receptor inhibitors provide potent (Ͼ80%) blockade of platelet aggregation dur- ing PCI, regardless of the platelet agonist. Although the EPIC study showed a 23% reduction in cumulative 6-month clinical events with abciximab ( p ϭ 0.001) (41), these events were primarily related to the prevention of early (Ͻ30 day) periprocedural events (20). Other studies have not shown a consistent reduction in clinical or angiographic restenosis with GP IIb-IIIa inhibitors (42). The need for late revascularization was not significantly lower (p ϭ 0.22) in patients receiv- ing stenting plus abciximab (8.7%) compared with patients receiving stenting ϩ placebo (10.6%) (28), although there was a significant reduction (p ϭ 0.02) in revascularization in diabetic patients assigned to stenting plus abciximab (8.1%) compared with patients receiving stenting plus placebo (16.6%) (28). This effect has been attributed to the enhanced activity of α v β 3 receptor activity in diabetic patients undergoing stent implantation. The intravenously administered GP IIb-IIIa inhibitors (e.g., abciximab, ep- tifibatide, and tirofiban) improve clinical outcomes within the first 30 days in patients undergoing PCI. These agents as a class reduce ischemic complications after PCI, including non-Q-wave MI and recurrent ischemia. Oral GPIIb-IIIa in- hibitors have not been effective in reducing early or late complications after PCI. It does not appear that GP IIb-IIIa inhibitors reduce the frequency of restenosis in nondiabetic patients; more study is needed to determine whether restenosis is reduced with abciximab in diabetic patients. These agents should be considered in all patients undergoing PCI, particularly in those patients with unstable angina, primary balloon PTCA or stent placement for acute MI, and in other patients at higher risk for ischemic complications after PCI. II. ANTITHROMBIN THERAPY Unfractionated heparin is used during PCI to prevent thrombus formation at the site of arterial injury and on the equipment used for PCI (44). Other antithrombin- III-dependent agents (i.e., low-molecular-weight heparins) and antithrombin-III- independent agents (i.e., hirudin, hirulog, and argatroban) have also been used during PCI, but have not yet achieved widespread use. Patients with acute coro- nary syndromes may also benefit from prolonged (Ͼ24-h) heparin therapy alone before PCI (45) or in combination with GP IIb-IIIa inhibitors (46–48). A. Unfractionated Heparin Activated partial thromboplastin times (aPTTs) are not useful for monitoring anti- coagulation intensity during PCI, as large amounts of unfractionated heparin, greater than the aPTT assay can analyze, are required to prevent thrombus forma- 180 Popma and Askari tion during arterial manipulations (49). Instead, near patient (also known as point of care) activated clotting time (ACT) monitoring is used to facilitate unfraction- ated heparin dose titration during PCI (50). ACT responses have shown marked variability in patients who received a non-weight-adjusted unfractionated heparin bolus. These differences have been attributed to patient-to-patient differences in heparin sensitivity and clearance, body weight, nitroglycerin use, and coexisting conditions that predispose to heparin resistance (e.g., heparin antibodies, oral contraceptive use, endocarditis, disseminated intravascular coagulation, and placement of an intra-aortic balloon pump). Patients with unstable angina and those with complex coronary lesions (irregular borders, overhanging edges, or filling defects) also have higher heparin dosing requirements (51). Heparin resis- tance may also be a marker of high-risk anatomy (52). Two retrospective studies have related the ACT value to clinical outcome after PCI (53,54). In one study, patients who had complications after PCI had lower mean baseline ACT (Hemo Tec) values after the initial heparin bolus and at the end of the procedure than those without complications (54). In another study, patients with abrupt closure had a lower mean ACT (Hemochron) at the time of first balloon inflation than those without this complication (352 s vs. 388 s, respectively; p Ͻ 0.002) (53). An inverse relationship was shown between in-laboratory ACT values and the probability of abrupt closure ( p ϭ 0.018) (53). Higher ACT levels (55) and other markers of excess anticoagulation (56) also may serve as independent predictors of bleeding complications after PCI, al- though this relationship has not been confirmed. These studies have formed the empiric recommendations of target ACT levels during PCI. With the availability of coronary stents, some recent studies show that lower dose heparin during PCI may also be safe and effective. In a series of 1375 consecutive patients undergoing PCI, low-dose bolus heparin (5000 IU) with early (Ͻ12 h) postprocedural sheath removal was associated with infrequent fatal complications (0.3%), emergency CABG (1.7%), MI (3.3%), or repeat angio- plasty within 48 h (0.7%) (57). ACT levels were not available in this study. Lower dose unfractionated heparin may prevent excessive anticoagulation, but at this juncture monitoring a low-dose heparin strategy with ACTs seems prudent. Although weight-adjusted heparin seems to lower bleeding complications compared with fixed-dose heparin in association with GP IIb-IIIa inhibitor use (23), the advantage of weight-adjusted heparin over fixed-dose heparin in one randomized trial of 400 patients that did not use GP IIb-IIIa inhibitors appeared to relate only to early sheath removal. Patients assigned to fixed-dose heparin (15,000 IU) or weight-adjusted heparin (100 IU/kg) had similar clinical outcomes (95% success rates) (58). Use of the weight-adjusted heparin did result in earlier sheath removal and more rapid transfer to a stepdown unit (58). The following empiric recommendation can be made with respect to antico- agulation during PCI. Weight-adjusted heparin dosing regimens (70 to 100 IU/ Antithrombotic Therapy During PCI 181 kg) or gender-adjusted bolus heparin (7000 U for women and 8000 U for men) should be used in an attempt to avoid ‘‘overshooting’’ the ACT (35). Sufficient unfractionated heparin should be administered during PCI to achieve an ACT between 250 and 300 s using the HemoTec monitor and between 300 and 350 s using the Hemochron monitor (50). The ACT should be monitored frequently and additional, smaller heparin boluses of 2000 to 5000 IU should be given until the target ACT is achieved. Lower target ACT levels (Ͼ200 s) are adequate when GPIIb-IIIa inhibitors are used. A number of studies have now shown that routine use of intravenous heparin after PCI is no longer indicated (59,60). Early sheath removal is strongly encouraged when the ACT falls to less than 150 to 180 s. B. Low-Molecular-Weight Heparin Patients with unstable angina may now be treated with low-molecular-weight heparin (LMWH) and, on occasion, require PCI for ongoing symptoms (61). While it is difficult to monitor anticoagulation levels using LMWH during PCI, conventional dosages of unfractionated heparin are generally recommended. It is important to note that conventional monitoring methods, such as the ACT, may underestimate the true degree of periprocedural anticoagulation. One pilot randomized trial of 60 patients undergoing PCI, treated with unfractionated hepa- rin or enoxaparin (1 mg/kg intravenously), showed no difference in safety be- tween the two anticoagulants (62). Similar favorable results with the use of intra- venous LMWH have been reported when this agent is used alone (NICE-1) or in combination with GPIIb-IIIa inhibitors (NICE-3 and NICE-4). Routine use of LMWH as the sole anticoagulant during PCI cannot be recommended at this time, pending the results of a large, multicenter trials evaluating the safety of LMWH compared with unfractionated heparin during PCI. C. Direct Thrombin Inhibitors Direct thrombin inhibitors have been evaluated during PCI as an alternative to heparin. In the Hirudin in a European Trial Versus Heparin in the Prevention of Restenosis after PTCA (HELVETICA) study (63), 1141 patients with unstable angina scheduled for PCI were treated with aspirin and then randomly assigned to bolus heparin (10,000 U) plus infusion (15 U/kg/h for 24 h), hirudin bolus (40 mg ϩ intravenous infusion, 0.2 mg/kg/h for 24 h) or hirudin bolus (40 mg plus intravenous infusion, 0.2 mg/kg/h for 24 h), followed by subcutaneous injec- tion (40 mg twice daily) for an additional 3 days. Hirudin use was associated with a 39% reduction in early cardiac events (p ϭ 0.023), although clinical out- comes were similar 7 months later in the three groups. Recombinant hirudin (Lepirudin) bolus (0.4 mg/kg) and infusion (0.15 mg/kg/h) and argatroban 182 Popma and Askari have now been approved for use in the United States in patients with heparin- induced thrombocytopenia. The direct thrombin inhibitor argatroban, unlike hirudin, does not require downward dose adjustment for renal insufficiency. None of the direct thrombin inhibitors have antidotes for bleeding. Another direct thrombin inhibitor, bivalirudin (AngioMax) was com- pared with unfractionated heparin in the Hirulog Angioplasty study, a randomized trial of 4098 patients with postinfarction or unstable angina undergoing PCI. After pretreatment with aspirin, patients were then assigned to heparin bolus (175 U/ kg bolus and 15 U/kg/h infusion for 18 to 24 h) or bivalirudin bolus (1.0 mg/ kg bolus and 2.5 mg/kg/h infusion for 4 h followed by 0.2 mg/kg/h for 14 to 20 h) (64). Bivalirudin did not reduce the likelihood of in-hospital death, Q-wave or non-Q-wave MI, or emergency CABG, although it did reduce the likelihood of bleeding complications (OR ϭ 0.4; p Ͻ 0.001) (64). In a prospectively stra- tified cohort of 704 patients with post-MI angina, bivalirudin therapy did result in lower rates of major ischemic complications (9.1% vs. 14.2% in heparin-treated patients; p ϭ 0.04), and lower rates of bleeding (3.0% vs. 11.1% in heparin- treated patients; p Ͻ 0.001). Bivalirudin has been approved by the Food and Drug Administration for use as an alternative to unfractionated heparin in patients undergoing PCI in the United States. D. Antithrombin Therapy for the Prevention of Restenosis After PCI Neither intravenous heparin (59) subcutaneous (65) unfractionated heparin, nor low-molecular-weight heparins, including enoxaparin, reviparin, nadroparin, and fraxiparin (66–68), prevent restenosis after PCI. Antithrombin-III-independent thrombin inhibitors, such as bivalirudin (69), hirudin (63), and long-term warfarin (70), also have had little effect on the prevention of restenosis. The safety of PCI has advanced substantially over the past several years, owing to both improvements in the techniques of coronary revascularization (e.g., coronary stents) and the availability of novel adjunct pharmacology (e.g., GP IIb-IIIa inhibitors). This review has focused on the advances that have been achieved with antithrombotic agents during PCI. The most dramatic advances have been with the GP IIb-IIIa inhibitors, which as a class have achieved a 30 to 50% reduction in 30-day clinical events, and with the use of clopidogrel, which has reduced the occurrence of subacute stent thrombosis to Ͻ1% in most centers. There has also been a steady advance in our understanding of the use of unfrac- tionated heparin during PCI. Near-patient monitoring has allowed the titration of unfractionated heparin, avoiding excessive anticoagulation, which may result in bleeding complications, and empiric guidelines have been established. Newer antithrombins, including LMWH, have been evaluated during PCI, but only the Antithrombotic Therapy During PCI 183 antithrombin III-independent bivalirudin has been approved for clinical use as an alternative to unfractionated heparin. No antithrombotic agent has been shown thus far to reduce restenosis, although abciximab may lower the restenosis rates in diabetic patients undergoing stent implantation. During the next few years, we will witness continued rapid evolution of the pharmacological regimens during PCI. REFERENCES 1. Schwartz L, Bourassa M, Lesperance J, Aldridge H, Kazim F, Salvatori V, et al. Aspirin and dipyridamole in the prevention of restenosis after percutaneous translu- minal coronary angioplasty. N Engl J Med 1988; 318:1714–1719. 2. White C, Chaitman B, Lassar T, Marcus M, Chisholm R, Knudson M, et al. Anti- platelet agents are effective in reducing the immediate complications of PTCA. Re- sults of the ticlopidine multicenter trial (abstr). Circulation 1987; 76:IV–400. 3. Lembo NJ, Black, AJ, Roubin GS, Wilentz JR, Mufson LH, Douglas JS, Jr., et al. Effect of pretreatment with aspirin versus aspirin plus dipyridamole on frequency and type of acute complications of percutaneous transluminal coronary angioplasty. Am J Cardiol 1990; 65:422–426. 4. Gregorini L, Marco J, Fajadet J, Bernies M, Cassagneau B, Brunel P, et al. Ticlopi- dine and aspirin pretreatment reduces coagulation and platelet activation during cor- onary dilation procedures. J Am Coll Cardiol 1997; 29:13–20. 5. Schomig A, Neumann FJ, Kastrati A, Schuhlen H, Blasini R, Hadamitzky M, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the place- ment of coronary-artery stents. N Engl J Med 1996; 334:1084–1089. 6. Leon M, Baim D, Popma J, Gordon P, Cutlip D, Ho K, et al. A clinical trial compar- ing three antithrombotic-drug regimens after coronary-artery stenting. N Engl J Med 1998; 339:1665–1671. 7. Bennett C, Weinberg P, Rozenberg-Ben-Dror K, et al. Thrombocytopenic purpura associated with ticlopidine. Ann Intern Med 1998; 128:541–544. 8. Szto G, Linnemeier T, Lewis S. Safety of 10 days of ticlopidine after coronary stenting—A randomized comparison with 30 days: Strategic ALternatives with Ticlopidine in Stenting Study (SALTS) (abstr). J Am Coll Cardiol 1998; 31:352A. 9. Berger P, Grill D, Melby S, et al. Can ticlopidine be safely discontinued two weeks after coronary stent placement (abstr). J Am Coll Cardiol 1998; 31:458A. 10. Coukell AJ, Markham A. Clopidogrel. Drugs 1997; 54:745–750. 11. The CAPRIE Committee. A randomised, blind, trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1996; 348:1239–1339. 12. Bertrand M. CLASSICS Study. Circulation 2000, in press. 13. Moussa I, Oetgen M, Roubin G, Colombo A, Wang X, Iyer S, et al. Effectiveness of clopidogrel and aspirin versus ticlopidine and aspirin in preventing stent thrombo- sis after coronary stent implantation. Circulation 1999; 99:2364–2366. 14. Bennett C, Connors J, Carwile J. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 2000; 342:1773–1777. 184 Popma and Askari 15. de Feyter P, van den Brand M, Jaarman G, van Domburg R, Serruys P, Suryapranata H. Acute coronary artery occlusion during and after percutaneous transluminal coro- nary angioplasty: Frequency, prediction, clinical course, management and follow- up. Circulation 1991; 83:927–936. 16. Myler RK, Shaw RE, Stertzer SH, Hecht HS, Ryan C, Rosenblum J, et al. Lesion morphology and coronary angioplasty: current experience and analysis. J Am Coll Cardiol 1992; 19:1641–1652. 17. Lincoff AM, Popma JJ, Ellis SG, Hacker JA, Topol EJ. Abrupt vessel closure com- plicating coronary angioplasty: clinical, angiographic and therapeutic profile. J Am Coll Cardiol 1992; 19:926–935. 18. Ruggeri Z. Receptor-specific antiplatelet therapy. Circulation 1989; 80:1920–1922. 19. Phillips D, Charo I, Parise L, Fitzgerald L. The platelet membrane glycoprotein IIb- IIIa complex. Blood 1988; 71:831–843. 20. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. The EPIC Investiga- tion. N Engl J Med 1994; 330:956–961. 21. Lincoff AM, Califf RM, Anderson KM, Weisman HF, Aguirre FV, Kleiman NS, et al. Evidence for prevention of death and myocardial infarction with platelet mem- brane glycoprotein IIb/IIIa receptor blockade by abciximab (c7E3 Fab) among pa- tients with unstable angina undergoing percutaneous coronary revascularization. EPIC Investigators. Evaluation of 7E3 in Preventing Ischemic Complications. J Am Coll Cardiol 1997; 30:149–156. 22. Brener SJ, Barr LA, Burchenal JE, Katz S, George BS, Jones AA, et al. Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. ReoPro and Primary PTCA Organiza- tion and Randomized Trial (RAPPORT) Investigators. Circulation 1998; 98:734– 741. 23. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low- dose heparin during percutaneous coronary revascularization. The EPILOG Investi- gators [see comments]. N Engl J Med 1997; 336:1689–1696. 24. Mak KH, Challapalli R, Eisenberg MJ, Anderson KM, Califf RM, Topol EJ. Effect of platelet glycoprotein IIb/IIIa receptor inhibition on distal embolization during percutaneous revascularization of aortocoronary saphenous vein grafts. EPIC Inves- tigators. Evaluation of IIb/IIIa platelet receptor antagonist 7E3 in preventing isch- emic complications. Am J Cardiol 1997; 80:985–988. 25. Mathew V, Grill D, Scott C, Grantham J, Ting H, Garratt K, et al. The influence of abciximab use on clinical outcome after aortocoronary vein graft interventions. J Am Coll Cardiol 1999; 34:1163–1169. 26. Muhlestein JB, Karagounis LA, Treehan S, Anderson JL. ‘‘Rescue’’ utilization of abciximab for the dissolution of coronary thrombus developing as a complication of coronary angioplasty. J Am Coll Cardiol 1997; 30:1729–1734. 27. The EPISTENT Investigators. Randomised placebo-controlled and balloon-angio- plasty-controlled trial to assess safety of coronary stenting with use of platelet glyco- protein-IIb/IIIa blockade. The EPISTENT Investigators. Evaluation of Platelet IIb/ IIIa Inhibitor for Stenting. Lancet 1998; 352:87–92. 28. Lincoff A, Califf R, Moliterno D, Ellis S, Ducas J, Kramer J, et al. Complementary Antithrombotic Therapy During PCI 185 clinical benefits of coronary artery stenting and blockade of platelet glycoprotein IIb/IIIa receptors. N Engl J Med 1999; 341:319–327. 29. The IMPACT-II Investigators. Randomised placebo-controlled trial of effect of ep- tifibatide on complications of percutaneous coronary intervention: IMPACT-II. Inte- grilin to Minimise Platelet Aggregation and Coronary Thrombosis-II. Lancet 1997; 349:1422–1428. 30. The RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocar- dial infarction undergoing coronary angioplasty. The RESTORE Investigators. Ran- domized Efficacy Study of Tirofiban for Outcomes and REstenosis. Circulation 1997; 96:1445–1453. 31. Rao T, Pratt C, Berke A, Jaffe A, Ockene I, Schreiber T, et al. Thrombolysis in Myocardial Infarction (TIMI) trial, phase I: hemorrhagic manifestations and changes in fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988; 11:1–11. 32. Thornton M, Gruentzig A, Hollman J, King SI, Douglas J. Coumadin and aspirin in prevention of recurrence after transluminal coronary angioplasty: A randomized study. Circulation 1984; 69:721–727. 33. Taylor R, Gibbons F, Cope G, Cumpston G, Mews G, Luke P. Effects of low-dose aspirin on restenosis after coronary angioplasty. Am J Cardiol 1991; 68:874–878. 34. Schwartz L, Lesperance J, Bourassa MG, Eastwood C, Kazim F, Arafah M, et al. The role of antiplatelet agents in modifying the extent of restenosis following percu- taneous transluminal coronary angioplasty. Am Heart J 1990; 119:232–236. 35. Popma JJ, Weitz J, Bittl JA, Ohman EM, Kuntz RE, Lansky AJ, et al. Antithrom- botic therapy in patients undergoing coronary angioplasty. Chest 1998; 114:728S– 741S. 36. Serruys PW, Rutsch W, Heyndrickx GR, Danchin N, Mast EG, Wijns W, et al. Prevention of restenosis after percutaneous transluminal coronary angioplasty with thromboxane A2-receptor blockade. A randomized, double-blind, placebo-con- trolled trial. Coronary Artery Restenosis Prevention on Repeated Thromboxane-An- tagonism Study (CARPORT). Circulation 1991; 84:1568–1580. 37. Savage M, Goldberg S, Macdonald R, Bass T, Margolis J, Whitworth H, et al. Multi- hospital Eastern Atlantic restenosis trial II: A placebo-controlled trial of thrombox- ane blockade in the prevention of restenosis following coronary angioplasty. Am Heart J 1991; 122:1239–1244. 38. Serruys PW, Klein W, Tijssen JP, Rutsch W, Heyndrickx GR, Emanuelsson H, et al. Evaluation of ketanserin in the prevention of restenosis after percutaneous translu- minal coronary angioplasty. A multicenter randomized double-blind placebo-con- trolled trial. Circulation 1993; 88:1588–601. 39. Knudtson ML, Flintoft VF, Roth DL, Hansen JL, Duff HJ. Effect of short-term prostacyclin administration on restenosis after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1990; 15:691–697. 40. Raizner A, Hollman J, Abukhalil J, Demke D. Ciprostene for restenosis revisited: Quantitative analysis of angiograms (abstr). J Am Coll Cardiol 1993; 21:321A. 41. Topol EJ, Califf RM, Weisman HF, Ellis SG, Tcheng JE, Worley S, et al. Random- ised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for 186 Popma and Askari reduction of clinical restenosis: results at six months. The EPIC Investigators. Lancet 1994; 343:881–886. 42. Gibson CM, Goel M, Cohen DJ, Piana RN, Deckelbaum LI, Harris KE, et al. Six- month angiographic and clinical follow-up of patients prospectively randomized to receive either tirofiban or placebo during angioplasty in the RESTORE trial. Ran- domized Efficacy Study of Tirofiban for Outcomes and Restenosis. J Am Coll Cardiol 1998; 32:28–34. 43. Marso S, Bhatt D, Tanguay J-F, Hammoud T, Sapp S, Robbins M, et al. Synergy of stenting plus abciximabl in diabetic patients: Persistence through 1-year follow- up from EPISTENT (abstr). Circulation 1999; 100:I–365. 44. Grayburn P, Willard J, Brincker M, Eichhorn E. In vivo thrombus formation on a guidewire during intravascular ultrasound imaging: Evidence for inadequate hepa- rinization. Cathet Cardiovasc Diagn 1991; 23:141–143. 45. Laskey MA, Deutsch E, Barnathan E, Laskey WK. Influence of heparin therapy on percutaneous transluminal coronary angioplasty outcome in unstable angina pectoris. Am J Cardiol 1990; 65:1425–1429. 46. The CAPTURE Investigators. Randomised placebo-controlled trial of abciximab be- fore and during coronary intervention in refractory unstable angina: the CAPTURE Study. Lancet 1997; 349:1429–1435. 47. The PRISM PLUS Investigators. Inhibition of the platelet glycoprotein IIb/IIIa re- ceptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. N Engl J Med 1998; 338:1488–1497. 48. The PURSUIT Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifi- batide in patients with acute coronary syndromes. The PURSUIT Trial Investigators. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Inte- grilin Therapy. N Engl J Med 1998; 339:436–443. 49. Dougherty K, Gaos C, Bush H, Leachman D, Ferguson J. Activated clotting times and activated partial thromboplastin times in patients undergoing coronary angio- plasty who receive bolus doses of heparin. Cathet Cardiovasc Diagn 1992; 26:260– 263. 50. Bowers J, Ferguson J. The use of activated clotting times to monitor heparin therapy during and after interventional procedures. Clin Cardiol 1994; 17:357–361. 51. Marmur J, Merlini P, Sharma S, Khaghan N, Torre S, Israel D, et al. Thrombin generation in human coronary arteries after percutaneous transluminal balloon an- gioplasty. J Am Coll Cardiol 1994; 24:1484–1491. 52. Marmur J, Sharma S, Kantrowitz N, Gupta V, Cocke T, Duvvuri S, et al. Angio- graphically complex lesions are associated with increased levels of thrombin genera- tion and activity following PTCA (abstr). J Am Coll Cardiol 1995; 25:155A. 53. Narins CR, Hillegass WB, Jr., Nelson CL, Tcheng JE, Harrington RA, Phillips HR, et al. Relation between activated clotting time during angioplasty and abrupt closure. Circulation 1996; 93:667–671. 54. Ferguson J, Dougherty K, Gaos C, Bush H, Marsh K, Leachman D. Relation between procedural activated clotting time and outcome after percutaneous transluminal coro- nary angioplasty. J Am Coll Cardiol 1994; 23:1061–1065. [...]... and Placebo-Controlled Evaluation J Am Coll Cardiol 19 96; 28:1437–1443 68 Lablanche JM, McFadden EP, Meneveau N, Lusson JR, Bertrand B, Metzger JP, 188 Popma and Askari et al Effect of nadroparin, a low-molecular-weight heparin, on clinical and angiographic restenosis after coronary balloon angioplasty: the FACT study Fraxiparine Angioplastie Coronaire Transluminale Circulation 1997; 96: 33 96 3402 69 ... follow-up? Up to 13-month follow-up is available on 225 patients and 266 vessels treated percutaneously in the UAB-LHH group No patients suffered a major stroke The minor stroke rate was 1.7%, and one patient died of a noncerebrovascular cause Although comparison of these data to the NASCET group is difficult, some interesting points can be made By subtracting the 30-day NASCET events from the overall 3 6- month... has been examined and is the impetus for aggressive treatment strategies Among 3000 patients with a history of recent TIA in the Dutch TIA trial, entrants were randomized to treatment with low- or moderate-dose aspirin (49) After 36 months, the risk of nonfatal stroke was 5.7% in the low-dose group and 6. 9% in the high-dose group Given the natural history of cerebrovascular disease and the unknown effects... technical success rate of 96% , with a 3% initial stroke rate and 2% mortality The overall complication rate was esti- Obstructive Atherosclerotic Peripheral Arterial Disease 201 mated as 16% , including such complications as stroke, hemorrhage, infection, Horner’s syndrome, graft thrombosis, and anesthetic-related problems Overall, open-chest procedures had a higher morbidity and mortality than extrathoracic... Investigators N Engl J Med 1995; 333: 764 – 769 65 Brack MJ, Ray S, Chauhan A, Fox J, Hubner PJ, Schofield P, et al The Subcutaneous Heparin and Angioplasty Restenosis Prevention (SHARP) trial Results of a multicenter randomized trial investigating the effects of high dose unfractionated heparin on angiographic restenosis and clinical outcome J Am Coll Cardiol 1995; 26: 947–954 66 Faxon DP, Spiro TE, Minor S,... (51) The 30day follow-up showed a benefit of medical therapy with a 5.8% rate of all stroke and death in the surgical group, and a 3 .6% risk in the medical group As with the ECST data, the 3 6- month death rate did not differ significantly between groups in the NASCET study (9.9% surgical vs 12.7% surgical) Again, the majority of these deaths were cardiovascular However, by 3 6- month follow-up, the total stroke... unusable for bypass surgery, and in patients with more proximal interventions with the hope of maintaining adequate distal runoff (12) Superior long-term patency rates after proximal interventions and saphenous Figure 3 Percutaneous treatment of femoral and tibial disease Short-segment stenoses and occlusions of the superficial femoral artery are readily approached This 4 6- year-old diabetic smoker developed... arteries Radiology 1990; 177: 565 – 569 15 Hanna GP, Fujise K, Kjellgren O, et al Infrapopliteal transcatheter interventions for limb salvage in diabetic patients: importance of aggressive interventional approach and role of transcutaneous oximetry J Am Coll Cardiol 1997; 30 :66 4 66 9 16 Bookstein JJ, Abrams H, Buenger R, et al Radiologic aspects of renovascular hypertension Part 2: the role of intravenous... 300: 569 –572 24 Losino F, Zuccala A, Busato F, Zucchelli P Renal artery angioplasty for renovascular hypertension and preservation of renal function: long-term angiographic and clinical follow-up Am J Roentgenol 1994; 162 :853–857 25 Jensen G, Zachrisson B-F, Denlin K, Volkmann R, Aurell M Treatment of renovascular hypertension: one year results of renal angioplasty Kidney Int 1995; 48: 19 36 1945 26 Rundback... femoropopliteal stenoses and the recanalization of superficial femoral occlusions has been reasonable, concerns regarding high restenosis rates persist Henry et al report an 11% restenosis rate in SFA lesions and 20% for popliteal lesions at 6- month angiographic follow-up (7) All lesions were treated with stent placement The 4-year patency rates among the same cohort were 65 % for SFA lesions and 50% for popliteal . IIb- IIIa blockade (EPILOG) trial randomly assigned 2792 patients who were treated with aspirin to standard-dose, weight-adjusted (100 U/kg bolus) heparin and pla- cebo, standard-dose, weight-adjusted. injury and on the equipment used for PCI (44). Other antithrombin- III-dependent agents (i.e., low-molecular-weight heparins) and antithrombin-III- independent agents (i.e., hirudin, hirulog, and. subcutaneous (65 ) unfractionated heparin, nor low-molecular-weight heparins, including enoxaparin, reviparin, nadroparin, and fraxiparin (66 68 ), prevent restenosis after PCI. Antithrombin-III-independent thrombin