-Differential antithrombotic therapy in patients with low and high PTCA risk-

Acute coronary occlusion as well as restenosis still represent the major limitations of coronary interventions. Either event seems to be related to thrombus formation. The purpose of this overview is to summarize the current status of the usefulness of conventional and newer antithrombotic drugs regarding the prevention of acute occlusion and restenosis (excluding stents). ANTICOAGULATION: For ethical reasons, no placebo-controlled studies were conducted to prove the usefulness of heparin in preventing acute occlusions. The dosage mostly used is 10,000 U, although a relationship between dosage and complication rate has not been documented. A prolonged heparin infusion in patients with low risk and uncomplicated PTCA has no advantages. Restenosis is not influenced by prolonged infusion of heparin or administration of coumadin as well. Low molecular weight heparin is currently under investigation. Hirudin and hirulog have shown promising results with less acute occlusions; however, their therapeutic range must be considered. ANTIAGGREGATION: In controlled studies, ASA significantly reduced acute occlusions during PTCA when given in addition to heparin. Ticlopidin is as effective as ASA, but due to its side effects should only be administered when contraindications to ASA exist. ASA significantly reduced restenosis in only 1 of 4 studies with limited number of patients. Thromboxane inhibitors such as ridogrel or clopidogrel showed promising initial results. Trapidil significantly reduced restenosis in 2 studies; quantitative stenosis analysis, however, was not performed. Inhibition of platelets by glycoprotein (GP) IIb/IIIa receptor antagonists represents an innovative therapeutic concept: numerous controlled trials have documented a significant reduction in cardiac ischemic events and therefore indirectly in restenosis rates. The recombinant monoclonal antibody c7E3 Fab seems to be more effective than the synthetic integrelin. Unfortunately, efficacy appears to be in direct relationship to the risk of bleeding complications. The clinical role of oral GP IIb/IIIa inhibitors has yet to be established. For patients with high risk PTCA, the use of hirudin instead of heparin as well as the addition of GP IIb/IIIa inhibitors should be considered.     

Tirofiban. A review of its use in acute coronary syndromes

Tirofiban is an intravenously administered nonpeptide glycoprotein IIb/IIIa receptor antagonist which specifically inhibits fibrinogen-dependent platelet aggregation and prolongs bleeding times in patients with acute coronary syndromes. Adenosine diphosphate (ADP)-induced platelet aggregation returns to near-baseline levels within 4 to 8 hours after cessation of a tirofiban infusion, a finding consistent with the drug's elimination half-life of approximately 2 hours. Three large clinical trials have shown that, when administered with a standard heparin and aspirin regimen, tirofiban reduces the risk of ischaemic complications in patients with unstable angina/non-Q-wave myocardial infarction (MI) and in patients undergoing percutaneous revascularisation. In PRISM-PLUS, a study involving 1915 patients with unstable angina/non-Q-wave MI, administration of intravenous tirofiban (0.4 microgram/kg/min loading dose for 30 minutes followed by a 0.10 microgram/kg/min infusion) with heparin for at least 48 (mean 71.3) hours reduced the 7-day risk of the composite end-point of MI, death and refractory ischaemia by 32% compared with heparin alone. The between-group risk reduction remained significant at 30 days (22%) and 6 months (19%). Similarly, in high-risk patients undergoing coronary angioplasty in RESTORE, the addition of tirofiban (10 micrograms/kg bolus in the 3 minutes prior to intervention followed by 0.15 microgram/kg/min for 36 hours) to a standard heparin regimen significantly reduced the risk of ischaemic complications by 38% on day 2 and 27% on day 7 compared with heparin alone. Although interim analysis in PRISM-PLUS showed that the use of tirofiban without heparin increased the 7-day risk of death compared with heparin alone, this finding was inconsistent with the effects of tirofiban on the risk of death in PRISM, a study involving 3232 patients with unstable angina/non-Q-wave MI. Tirofiban is generally well tolerated. Bleeding complications were the most commonly reported events associated with tirofiban in clinical trials, but the rate of major bleeding in tirofiban recipients was not significantly different from that reported with heparin. Thrombocytopenia (platelet count < 90,000 cells/microliter) occurred slightly more frequently with tirofiban (with or without heparin) than with heparin alone. CONCLUSIONS: Tirofiban reduces the risk of ischaemic complications in patients with unstable angina/non-Q-wave MI and high-risk patients undergoing revascularisation when used against a background of heparin and aspirin. Furthermore, the drug has an acceptable tolerability profile. Therefore, intravenous tirofiban is likely to be used as an adjunct to heparin and aspirin in patients with acute coronary syndromes including high-risk patients undergoing revascularisation.     

New anticoagulant strategies

The limitations of standard heparin have prompted the development of a variety of newer antithrombotic agents. In fact, a LMWH preparation has recently been approved for clinical use in North America. Of these novel preparations, LMWH, the direct thrombin inhibitors, and inhibitors of GPIIb-IIIa have been used clinically and are in advanced stages of evaluation. Not only is LMWH effective in the prevention of venous thromboembolic disease in high-risk patients, but its more predictable dose response makes it an ideal candidate for the treatment of venous thrombosis. Further studies are needed to determine whether LMWH is superior to standard heparin as adjunctive therapy in patients undergoing coronary thrombolysis or angioplasty. Particularly promising in the setting of arterial thrombosis are hirudin, hirulog, and 7E3. With the encouraging results reported to date, it is likely that these agents will soon find their way into the treatment armamentarium of arterial thrombosis.     

Use of abciximab during coronary angioplasty

The IIb-IIIa glycoprotein is the platelet receptor of fibrinogen and the final common pathway of platelet activation and aggregation. Abciximab is a Fab fragment of the chimeric monoclonal antibody (c7E3) interfering with the glycoprotein receptor. It is the only anti IIb-IIIa currently available, commercialized under the name of Reopro. Preliminary clinical data has been obtained with its use in high risk coronary angioplasty. The EPIC trial showed a 35% relative reduction of the principal combined criterion of judgement of cardiac morbidity and mortality at 1 month, a benefit even greater in acute coronary syndromes (-72%) than in programmed procedures for complex type C lesions (-10%). The incidence of severe bleeding was high (14%). The results of the CAPTURE trial could widen the indications of abciximab to include the period surrounding angioplasty for unstable angina as the use of Reopro in the 24 hours before the procedure significantly reduced the risk of ischaemic events (10.8% versus 16.4%). In programmed angioplasty, the EPILOG trial investigated the effects of adapting the dose of heparin and an infusion of abciximab to body weight early (4th to 6th hour) withdrawal of the arterial introducer without continuing heparin. Using a 70 IU/Kg dosage modulated to algorithms taking into account the ACT, the incidence of bleeding complications was reduced to 1.8%, the same as the control group, and the benefits with regards to ischaemic events were not only maintained but increased (a 56% reduction at 1 months). Utilization of abciximab would be supported by the Cost saving approach of the EPIC trial 3-years follow-up which showed presentation of the initial benefits.     

Differential inhibition of platelet aggregation induced by adenosine diphosphate or a thrombin receptor-activating peptide in patients treated with bolus chimeric 7E3 Fab: implications for inhibition of the internal pool of GPIIb/IIIa receptors

OBJECTIVES: This study sought to describe in detail the pharmacokinetics and pharmacodynamics of chimeric monoclonal 7E3 Fab (c7E3 Fab) and to compare platelet responses to adenosine diphosphate (ADP) and the 11-amino acid thrombin receptor-activating peptide (TRAP [SFLLRNPNDKY-NH2]) in patients undergoing elective coronary angioplasty. BACKGROUND: Inhibition of platelet aggregation with monoclonal antibody c7E3 Fab directed against glycoprotein (GP) IIb/IIIa has been shown to reduce ischemic complications after angioplasty and is being considered for treatment of other acute ischemic syndromes. METHODS: Patients undergoing elective coronary angioplasty received aspirin (325 mg orally), heparin (12,000 U intravenously) and a bolus of c7E3 Fab (0.25 mg/kg body weight). Surface GPIIb/IIIa receptor blockade and aggregation in response to 20 mumol/liter ADP, 5 micrograms/ml collagen and 7.5 and 15 mumol/liter TRAP were assessed. RESULTS: Surface GPIIb/IIIa receptor blockade by c7E3 Fab was 80% 2 h after injection and decreased to 50% at 24 h. Platelet aggregation in response to 20 mumol/liter ADP was inhibited by 73% at 2 h, and this inhibition decreased to 27% at 24 h. Platelet aggregation in response to 7.5 mumol/liter TRAP was inhibited by 53% at 2 h and 30% at 24 h. In contrast, aggregation in response to 15 mumol/liter TRAP was inhibited only 37% at 2 h and 10% at 24 h (p < 0.001 and p = 0.006, respectively vs. 20 mumol/liter ADP). Addition of exogenous c7E3 Fab to platelet-rich plasma led to more complete inhibition of 7.5 mumol/liter TRAP-induced aggregation. CONCLUSIONS: After c7E3 Fab treatment, inhibition of platelet aggregation depends on the agonist and can be overcome by increased thrombin activity but is restored if additional c7E3 Fab is added to block additional GPIIb/IIIa receptors. This phenomenon may be related to an internal pool of GPIIb/IIIa receptors joining the surface membrane and has implications concerning the duration of therapy with c7E3 Fab for patients with unstable angina or acute myocardial infarction.     

Abciximab. An updated review of its use in ischaemic heart disease

Abciximab is a glycoprotein IIb/IIIa receptor antagonist that has proven to be of significant clinical value in improving patient outcome after percutaneous coronary revascularisation. Primarily, the drug inhibits platelet aggregation, but it may also have anticoagulant activity and other beneficial effects, such as inhibiting migration and promoting apoptosis of smooth muscle cells. Large well designed studies have found administration of abciximab (as an adjunct to heparin and aspirin) during percutaneous coronary revascularisation to significantly reduce the incidence of ischaemic complications occurring in the 30 days after the procedure. Significant benefit, particularly on the incidence of myocardial infarction, was still evident after 6 months in 2 of 4 major trials. Abciximab provides particular benefit in patients with unstable angina or myocardial infarction who are undergoing percutaneous coronary revascularisation. The benefits of the drug are additive to those achieved with coronary stenting. Very preliminary data suggest that abciximab may improve coronary blood flow after myocardial infarction and allow reperfusion to be achieved with reduced thrombolytic doses. Caution is required to minimise the risk of bleeding complications with the use of abciximab in combination with heparin and aspirin. Careful patient selection, use of an appropriate heparin regimen, early vascular sheath removal and meticulous femoral artery access site care are recommended. Thrombocytopenia can occur with abciximab treatment, but severe cases are uncommon (< 2% of patients) and can be treated with platelet transfusions. The high acquisition cost of abciximab may be partly or fully offset by the costs averted by the reduced incidence of ischaemic complications and need for urgent and/or repeat revascularisation in high risk patients who receive the drug. However, if bleeding complications occur, this adds to treatment costs. Cost effectiveness analyses generally support the use of abciximab in high risk patients. CONCLUSIONS: Abciximab can be recommended for the prevention of acute ischaemic events in most patients undergoing percutaneous coronary revascularisation, but careful patient selection and strict adherence to the recommended treatment protocol are required to reduce the risk of bleeding complications and thrombocytopenia. Its use in high risk patients is largely supported by pharmacoeconomic data. Further pharmacoeconomic information is needed to establish the drug as a standard of care for all patient groups. The indications for abciximab are likely to expand as more data on its use in acute coronary syndromes become available.     

Clinical trials of direct thrombin inhibitors in acute ischaemic syndromes

Unfractionated heparin is commonly used as standard therapy along with aspirin for the management of acute ischaemic syndromes. However, heparin has many limitations including a poor dose effect response and an inability to inactivate clot bound thrombin. Direct thrombin inhibitors inactivate clot bound thrombin and also prevent thrombin induced platelet aggregation. The prototypical direct thrombin inhibitor, hirudin, has been tested in the TIMI 9 and GUSTO II trials. These trials showed a 14% reduction in reinfarction at 30 days, but there was no effect on mortality or on the combined end point of death and nonfatal myocardial infarction (10.8% heparin versus 10.0% hirudin). More moderate bleeding occurred with hirudin than with intravenous heparin. Hirulog has been shown to increase the rate of TIMI grade 3 patency (from 35% to 48%, p = 0.03) at 90 minutes after streptokinase administration, and this is now being tested in a large mortality trial. Further trials are necessary to further test whether patient care can be improved by appropriate doses of these agents administered for an appropriate duration.     

Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. The EPIC Investigators

Restenosis after coronary angioplasty occurs in at least 30% of patients in the first six months and, as yet, there is no known treatment to decrease this event. We tested a monoclonal antibody Fab fragment (c7E3) directed against the platelet glycoprotein IIb/IIIa integrin, the receptor mediating the final common pathway of platelet aggregation, to see whether it reduced the frequency of clinical restenosis. Patients who had unstable angina, recent or evolving myocardial infarction, or high-risk angiographic morphology, were randomised to receive c7E3 bolus and a 12 hour infusion of c7E3 (708 patients), c7E3 bolus and placebo infusion (695 patients), or placebo bolus and placebo infusion (696 patients). With maintenance of the double-blind state, patients were followed-up for at least 6 months to determine the need for repeat angioplasty or surgical coronary revascularisation and the occurrence of ischaemic events. By 30 days, 12.8% of placebo bolus/placebo infusion patients had had a major ischaemic event (death, myocardial infarction, urgent revascularisation), compared with 8.3% of c7E3 bolus/c7E3 infusion patients, yielding a 4.5% difference (35% reduction, p = 0.008). At 6 months, the absolute difference in patients with major ischaemic event or elective revascularisation was 8.1% between placebo bolus/placebo infusion and c7E3 bolus/c7E3 infusion patients (35.1% vs 27.0%; 23% reduction p = 0.001). The favourable long-term effect was mainly due to less need for bypass surgery or repeat angioplasty in patients with an initial successful procedure, since need for repeat target vessel revascularisation was 26% less for c7E3 bolus/c7E3 infusion than for placebo treatment (16.5% vs 22.3%; p = 0.007). The c7E3 bolus/placebo infusion group had an intermediate outcome which was not significantly better than that of the placebo bolus/placebo infusion group. These results extend the benefit of c7E3 bolus/c7E3 infusion from reducing abrupt closure and acute-phase adverse outcomes to a diminished need for subsequent coronary revascularisation procedures. Because this therapy carries a risk of bleeding complications and has been studied only in high-risk angioplasty patients, further evaluation is needed before it can be applied to other patient groups.     

A risk-benefit assessment of abciximab in angioplasty

Advances in percutaneous coronary intervention (PCI) have allowed procedures to be performed on a variety of patients with a spectrum of challenging coronary anatomy. Abciximab has permitted further expansion and has made the procedure safer. Abciximab is a chimerised murine monoclonal antibody directed against the platelet glycoprotein (GP) IIb-IIIa receptor. Binding to this receptor inhibits platelet aggregation to a wide variety of biological agonists. It also binds to alphavbeta3 and leucocyte MAC-1 receptors; the biological significance of its affinity to these receptors is unclear. Abciximab has an extremely short plasma half-life. Since abciximab binds to the platelet GP IIb-IIIa receptor with great avidity it has an extremely long biological half-life. The use of abciximab is currently confined primarily to PCIs. The first large trial, EPIC, established that abciximab, given with aspirin (acetylsalicylic acid) and heparin, reduced the frequency of peri-procedural ischaemic events by 35% in high-risk patients. For this reduction a bolus of 0.25 mg/kg was followed by a 12-hour infusion of abciximab. However, the transfusion rate was doubled. A subsequent trial, EPILOG, indicated that reduction of the dose of heparin along with expeditious removal of arterial access sheaths, reduced the rate of haemorrhagic complications to a level comparable with placebo-treated patients. while also amplifying the reduction in ischaemic events. In a third trial, EPISTENT, this benefit was shown to include patients undergoing elective coronary stent implantation. Additional trials have demonstrated that the same effect is present in patients undergoing primary PCI for acute myocardial infarction and in patients undergoing PCI for refractory unstable angina pectoris. In the latter situation, treatment with abciximab for 18 to 24 hours preceding the intervention reduced the rate of myocardial infarction even before the procedure was begun. The rationale for the use abciximab is thus clearly established. Bleeding complications can be reduced by limiting the heparin dose, avoiding unneeded venous access site punctures, and expeditious removal of arterial sheaths. In emergency coronary artery bypass surgery, platelet transfusion reduces the number of receptors occupied per platelet and is likely to reduce the degree of postoperative bleeding. The cost of abciximab remains an issue; however, this is partially offset by the reduction in ischaemic complications and accompanying resource use. In patients undergoing elective coronary stenting, abciximab use reduced the long term rate of target vessel revascularisation. The degree to which this reduction results in further cost savings will require further analysis.     

Current approach in antithrombotic treatment during coronary interventions: specific thrombocyte aggregation inhibitors and direct thrombin antagonists in high-risk patients

Patients undergoing angioplasty (PTCA) for unstable angina, postinfarction angina, or complex coronary lesions represent a high risk group for ischemic complications. High dose heparin and aspirin are used routinely to prevent thrombotic complications. However, new approaches designed to avoid platelet aggregation, including development of specific platelet GP IIb/IIIa receptor antagonists and specific thrombin inhibitors, demonstrate a significant reduction of thrombotic events following coronary interventions compared to heparin alone. Bleeding complications are not increased if conjunctive heparin administration is weight-adjusted. Pathophysiology of acute coronary closure, mechanisms of action of the new anti-thrombotic drugs, and current and future clinical applications are discussed.     

Randomized, double-blind comparison of hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO). Hirulog Early Reperfusion/Occlusion (HERO) Trial Investigators

BACKGROUND: Thrombolytic therapy improves survival after myocardial infarction through reperfusion of the infarct-related artery. Thrombin generated during thrombolytic administration may reduce the efficacy of thrombolysis. A direct thrombin inhibitor may improve early patency rates. METHODS AND RESULTS: Four hundred twelve patients presenting within 12 hours with ST-segment elevation were given aspirin and streptokinase and randomized in a double-blind manner to receive up to 60 hours of either heparin (5000 U bolus followed by 1000 to 1200 U/h), low-dose hirulog (0.125 mg/kg bolus followed by 0.25 mg x kg(-1) x h(-1) for 12 hours then 0.125 mg x kg(-1) x h(-1)), or high-dose hirulog (0.25 mg/kg bolus followed by 0.5 mg x kg(-1) x h(-1) for 12 hours then 0.25 mg x kg(-1) x h(-1)). The primary outcome was Thrombolysis In Myocardial Infarction trial (TIMI) grade 3 flow of the infarct-related artery at 90 to 120 minutes. TIMI 3 flow was 35% (95% CI, 28% to 44%) with heparin, 46% (95% CI, 38% to 55%) with low-dose hirulog, and 48% (95% CI, 40% to 57%) with high-dose hirulog (heparin versus hirulog, P=.023; heparin versus high-dose hirulog, P=.03). At 48 hours, reocclusion had occurred in 7% of heparin, 5% of low-dose hirulog, and 1% of high-dose hirulog patients (P=NS). By 35 days, death, cardiogenic shock, or reinfarction had occurred in 25 heparin (17.9%), 19 low-dose hirulog (14%), and 17 high-dose hirulog patients (12.5%) (P=NS). Two strokes occurred with heparin, none with low-dose hirulog, and two with high-dose hirulog. Major bleeding (40% from the groin site) occurred in 28% of heparin, 14% of low-dose hirulog, and 19% of high-dose hirulog patients (heparin versus low-dose hirulog, P<.01). CONCLUSIONS: Hirulog was more effective than heparin in producing early patency in patients treated with aspirin and streptokinase without increasing the risk of major bleeding. Direct thrombin inhibition may improve clinical outcome.     

Anticoagulant effects of hirulog, a novel thrombin inhibitor, in patients with coronary artery disease

Selective thrombin inhibitors are a new class of antithrombotic drugs that, unlike heparin, can effectively inhibit clot-bound thrombin and escape neutralization by activated platelets. Hirulog is a 20 amino acid hirudin-based synthetic peptide that has shown promise in experimental models of thrombosis. Little information is available about the effects of hirulog in patients with coronary artery disease. Forty-five patients undergoing cardiac catheterization, who were taking aspirin, were randomized to receive either (1) hirulog, 0.05 mg/kg intravenous bolus followed by 0.2 mg/kg/hour intravenous infusion until the end of the catheterization; (2) hirulog, 0.15 mg/kg intravenous bolus followed by 0.6 mg/kg/hour intravenous infusion; or (3) heparin; 5,000 U intravenous bolus. Serial activated partial thromboplastin time (APTT), prothrombin time, activated clotting time and fibrinopeptide A were measured. Hirulog produced a dose-dependent prolongation of all coagulation parameters; the 0.6 mg/kg/hour dose prolonged the APTT to 218 +/- 50% of baseline after 2 minutes and 248 +/- 50% of baseline after 15 minutes. The half-life of the effect on APTT was 40 minutes. The hirulog blood level correlated well with the APTT, prothrombin time and activated clotting time (r = 0.77, 0.73, and 0.82 respectively, all p < 0.001). Both doses of hirulog potently suppressed the generation of fibrinopeptide A (p < 0.05). There were no major hemorrhagic, thrombotic or allergic complications in patients treated with hirulog or heparin. Thus, hirulog, a direct thrombin inhibitor, provides a predictable level of anticoagulation and appears to have a potent yet well-tolerated anticoagulant profile in patients with coronary artery disease.     

Inhibition of platelet-mediated, tissue factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody. Potential implications for the effect of c7E3 Fab treatment on acute thrombosis and "clinical restenosis"

The murine/human chimeric monoclonal antibody fragment (c7E3 Fab) blocks GPIIb/IIIa and alpha v beta 3 receptors, inhibits platelet aggregation, and decreases the frequency of ischemic events after coronary artery angioplasty in patients at high risk of suffering such events. Although inhibition of platelet aggregation is likely to be the major mechanism of c7E3 Fab's effects, since activated platelets facilitate thrombin generation, it is possible that c7E3 Fab also decreases thrombin generation. To test this hypothesis, the effects of c7E3 Fab and other antiplatelet agents were tested in a thrombin generation assay triggered by tissue factor. c7E3 Fab produced dose-dependent inhibition of thrombin generation, reaching a plateau of 45-50% inhibition at concentrations > or = 15 micrograms/ml. It also inhibited thrombin-antithrombin complex formation, prothrombin fragment F1-2 generation, platelet-derived growth factor and platelet factor 4 release, incorporation of thrombin into clots, and microparticle formation. Antibody 6D1, which blocks platelet GPIb binding of von Willebrand factor, had no effect on thrombin generation, whereas antibody 10E5, which blocks GPIIb/IIIa but not alpha v beta 3 receptors decreased thrombin generation by approximately 25%. Combining antibody LM609, which blocks alpha v beta 3 receptors, with 10E5 increased the inhibition of thrombin generation to approximately 32-41%. The platelets from three patients with Glanzmann thrombasthenia, who lacked GPIIb/IIIa receptors but had normal or increased alpha v beta 3 receptors, supported approximately 21% less thrombin generation than normal platelets. We conclude that thrombin generation initiated by tissue factor in the presence of platelets is significantly inhibited by c7E3 Fab, most likely in part through both GPIIb/IIIa and alpha v beta 3 blockade, and that this effect may contribute to its antithrombotic properties.     

Distinct effects of recombinant desulfatohirudin (Revasc) and heparin on plasma levels of fibrinopeptide A and prothrombin fragment F1.2 in unstable angina. A multicenter trial

BACKGROUND: Thrombin plays an important role in the pathogenesis of acute coronary thrombosis. We studied the effects of a direct thrombin inhibitor, recombinant desulfatohirudin, and heparin on plasma levels (at 0, 4, 12, and 24 hours) of fibrinopeptide A (FPA), which reflects thrombin action, and prothrombin fragment F1.2, which reflects thrombin generation, in patients with unstable angina. METHODS AND RESULTS: Patients were randomized to one of two doses of heparin (n = 50) (target activated partial thromboplastin time, 65 to 90 seconds or 90 to 110 seconds) or one of four doses of r-hirudin (n = 113) (0.05, 0.10, 0.20, or 0.30 mg.kg-1.h-1 by infusion). r-Hirudin induced a dose-dependent decline in plasma FPA. At 24 hours, FPA levels with 0.1- to 0.3-mg.kg-1.h-1 r-hirudin regimens were significantly lower than with 0.05 mg.kg-1.h-1 r-hirudin; levels with 0.1- to 0.2-mg.kg-1.h-1 r-hirudin regimens were lower than with both heparin regimens. Plasma F1.2 did not decline significantly during therapy with heparin or hirudin except at 0.3 mg.kg-1.h-1 hirudin. At 24 hours, they were higher with the 0.05-mg.kg-1.h-1 r-hirudin regimen than with other regimens. For comparable levels of thrombin generation (F1.2 levels), FPA levels were higher in heparin patients than in hirudin patients. For the same FPA values, the corresponding F1.2 values were higher in the hirudin group. CONCLUSIONS: Our findings provide evidence for distinct in vivo effects of the two agents and suggest that r-hirudin is a relatively more potent inhibitor of thrombin action but a less effective inhibitor of thrombin generation than heparin. The lower FPA levels in hirudin patients may reflect its ability to inactivate clot-bound thrombin. The relative clinical efficacies of the two agents need to be defined by clinical trials in progress.     

Administration of abciximab during percutaneous coronary intervention reduces both ex vivo platelet thrombus formation and fibrin deposition: implications for a potential anticoagulant effect of abciximab

Abciximab (c7E3 Fab, ReoPro), a platelet glycoprotein (GP) IIb/IIIa inhibitor, decreases acute ischemic complications after percutaneous coronary interventions. Recently, abciximab was shown to decrease thrombin generation in vitro in a static system. To assess whether abciximab can decrease fibrin formation in blood from patients, we quantified both platelet thrombi and fibrin deposition by using an ex vivo flow chamber model. We prospectively studied 18 consecutive patients who underwent percutaneous interventions for unstable coronary syndromes. Blood was perfused directly from the patient through an ex vivo perfusion chamber at a high shear rate, thus mimicking mildly stenosed coronary arteries. Perfusion chamber studies were performed when patients were being treated with heparin plus aspirin before the procedure (baseline) and then repeated after the procedure, when patients were on either aspirin plus heparin alone (group 1, no abciximab, control) or aspirin plus heparin plus abciximab (group 2, abciximab treated). Each patient served as his or her own control. Specimens were stained with combined Masson's trichrome-elastin and antibodies specific for fibrinogen, fibrin, and platelet GP IIIa. Total thrombus area and areas occupied by platelet aggregates and fibrin layers were quantified by planimetry. Group 1 demonstrated no significant change in thrombus area before versus after the procedure; in contrast, treatment with abciximab reduced total thrombus area by 48% in group 2 (after the procedure versus baseline, P=0.01). This decline was due to significant reductions in both platelet aggregates (55%, P=0.005) and fibrin layers (45%, P=0.03). The addition of abciximab to heparin and aspirin in patients undergoing coronary interventions significantly decreases ex vivo thrombus formation on an injured vascular surface. Treatment with abciximab appears to reduce both the platelet and the fibrin thrombus components. This finding supports a potential role for GP IIb/IIIa receptor blockade in decreasing fibrin formation in addition to inhibition of platelet aggregation. Thus, potent inhibitors of GP IIb/IIIa may also act as anticoagulants.     

Randomized comparison of direct thrombin inhibition versus heparin in conjunction with fibrinolytic therapy for acute myocardial infarction: results from the GUSTO-IIb Trial. Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO-IIb) Investigators

OBJECTIVES: We sought to show that hirudin might interact differently with streptokinase (SK) and tissue-type plasminogen activator (t-PA), which could reduce the incidence of death or reinfarction at 30 days. BACKGROUND: In a large-scale trial of patients with acute coronary syndromes, hirudin provided modest benefit compared with heparin. However, the interaction with thrombolytic agents was not specifically assessed. METHODS: Patients with symptoms of acute myocardial infarction and electrocardiographic ST segment elevation were treated with thrombolytic therapy and randomly assigned to receive hirudin or heparin. RESULTS: A total of 2,274 patients received t-PA, and 1,015 received SK. Baseline characteristics were balanced by antithrombin assignment. Among SK-treated patients, death or reinfarction at 30 days occurred more often in those treated with adjunctive heparin (14.4%) rather than hirudin (8.6%, odds ratio [OR] 1.78, 95% confidence interval [CI] 1.20 to 2.66, p = 0.004). Among t-PA-treated patients, the rates were 10.9% with heparin and 10.3% with hirudin (OR 1.06, 95% CI 0.81 to 1.38, p = 0.68; for treatment heterogeneity: chi-square 4.20, degrees of freedom [df] 1, p = 0.04). After adjustment for baseline differences between thrombolytic groups, the rates were 9.1% for SK with hirudin, 10.3% for t-PA with hirudin, 10.5% for t-PA with heparin and 14.9% for SK with heparin (for treatment heterogeneity: chi-square 4.5, df 1, p = 0.03), suggesting that the beneficial treatment effect of hirudin was limited to the SK-treated patients. CONCLUSIONS: Hirudin interacts favorably with SK but not t-PA, highlighting the importance of thrombin activity after SK therapy and the potential for simulating the effects of a more potent fibrinolytic agent through direct antithrombin therapy.     

Agelasines H and I, 9-methyladenine-containing diterpenoids from an Agelas sponge

Direct anti-thrombin inhibitors such as hirudin have theoretical advantages over heparin. Two large studies in acute coronary syndromes were designed to test the thrombin hypothesis by demonstrating improved outcomes in hirudin treated patients. TIMI 9 assessed the effect of hirudin in patients with ST elevation receiving thrombolytic therapy. GUSTO 2 assessed the full spectrum of acute coronary syndromes of ST elevation and non-ST elevation. Over 15,000 patients were entered into the studies and no major benefit was demonstrated for hirudin. This may, however, relate to endpoints measured and the timing of the anti-thrombin.     

Reduction of in-hospital complications after elective percutaneous transluminal coronary angioplasty using a combined pretreatment with ticlopidine and aspirin

OBJECTIVES: In a retrospective study the effect of a combined pretreatment using ticlopidine and aspirin (ASA) in patients undergoing elective PTCA procedures was investigated with respect to in-hospital complications of PTCA and with respect to the efficacy in avoiding a subacute stent thrombosis in case of stent implantation. The systematically performed pretreatment with ticlopidine and ASA takes the delayed begin of full antiplatelet effect of ticlopidine into account. METHODS: 1108 consecutive patients (group 1) underwent elective PTCA without pretreatment with ticlopidine. In case of stent implantation oral anticoagulation was initiated in this group. In 758 consecutive patients (group 2) with elective PTCA, a combined regimen with ticlopidine and ASA was initiated at least 24 h prior to PTCA and was continued in case of stent implantation. The rate of procedural success, necessary reinterventions, cardiac events (myocardial infarction, death) and complications as well as the rate of subacute stent thrombosis in the subgroups with stent implantation were evaluated. RESULTS: The number of patients without in-hospital cardiac complications (myocardial infarction, coronary artery bypass surgery, death) and without re-PTCA interventions was 92.8% in group 1 and 96.3% in group 2 (p < 0.005). Especially the rate of necessary reinterventions was significantly reduced in group 2 compared with group 1 (5.3% vs. 2.4%, p < 0.001). Cardiac events were reduced in group 2 (myocardial infarction: 2.0% vs. 1.1%, coronary artery bypass graft: 0.8% vs. 0.5%, exitus: 0.5% vs. 0%), the incidence of bleeding complications was similar in both groups (2.5% vs. 2.4%). The combined pretreatment with ticlopidine and ASA with a stent implantation rate of 16.4% in group 2 was effective to avoid a subacute stent thrombosis (1.6%, independent of the indication to stent implantation). One patient of 758 in group 2 had allergic reactions to ticlopidine. CONCLUSIONS: The "prophylactic" pretreatment with ticlopidine and ASA in combination with a higher rate of stent implantation reduces necessary reinterventions and cardiac events after PTCA and is effective to avoid subacute stent thrombosis without increase of complications, especially bleeding complications. Thus, this pretreatment can be proposed even in patients scheduled for elective PTCA without planned stent implantation to reduce the interval between a necessary unforeseen stent implantation and the full treatment effects of ticlopidine.     

New antithrombotic agents

The wide range of compounds currently being developed is the result of the continuing need for validated new antithrombotic agents. The prevention and treatment of venous thrombosis is predominated by anticoagulants: low molecular weight heparins, and potentially new antithrombin agents including hirudin. The effectiveness of new antiplatelet agents, and particularly c7E3 and integrelin, confirms the hypothesis concerning the role played by platelets in thrombogenesis in coronary arteries. But, due to the proaggregating effect of thrombin, anticoagulants could also have an important role in preventing arterial clots, either when given alone or in combination. Finally, the development of antithrombin and anti-platelet-glycoprotein IIb IIIa given orally is one of the major objectives of current research. Until the ideal antithrombotic agent is discovered, multiple-drug regimens combining anticoagulants and/or antiplatelet agents could be proposed in patients with a very high risk of thrombosis. Such regimens must taken into account the increased risk of bleeding and be adapted on the basis of careful laboratory surveillance.     

Late results of percutaneous transluminal coronary angioplasty of two or more major native coronary arteries

Of 613 consecutive patients with multivessel coronary artery disease (CAD) undergoing revascularization, 521 patients (85%) underwent primary management with percutaneous transluminal coronary angioplasty (PTCA). To examine long-term outcome in a series of patients often referred for coronary artery bypass graft (CABG) surgery, all patients undergoing multivessel dilations were identified for late follow-up analysis (n = 161). Mean age was 65 years; 54 patients (34%) were women. Four hundred fifty-five of 502 lesions (90.6%) were successfully dilated. Major in-hospital procedural complications occurred in 6 patients (3.7%), including death in 3 (1.9%), nonfatal Q-wave myocardial infarction in 2 (1.2%), and CABG in 1 (0.6%). Final follow-up data were available in 159 patients (99%) at a mean of 39 +/- 18 months. Including in-hospital events, actuarial 3-year survival was 93%, and 3-year infarct-free survival was 90%. At final follow-up, 143 of 146 patients alive (98%) were angina free. Crossover to CABG was required in 25 patients (16%). Repeat PTCA was performed in 67 patients (42%) (mean 1.7 PTCAs/patient, range 1 to 7). PTCA is an effective therapeutic alternative in the management of most patients with multivessel CAD requiring revascularization. A strategy using multiple repeated PTCA procedures when necessary results in prolonged infarct-free survival, with long-term freedom from angina and limited crossover to CABG.