Bleeding complications with new antithrombotics used in ischaemic heart disease

Despite adjunctive therapy with heparin and aspirin, patients undergoing percutaneous transluminal coronary angioplasty (PTCA) continue to be at risk of abrupt vessel closure and acute ischaemic events. In an attempt to overcome the limitations of traditional antithrombotics, more potent agents have been developed, including direct thrombin inhibitors (e.g., hirudin and hirulog) and new antiplatelet agents [e.g., the glycoprotein IIb/IIIa receptor inhibitor c7E3 Fab (ReoProTM)]. Initial phase-III trials of hirudin in patients with acute coronary syndromes identified an excess incidence of major bleeding complications. Some of these trials have been recommenced using lower doses. Reports on phase-III trials of hirulog should be forthcoming soon. Of the new agents, the chimeric monoclonal antibody fragment c7E3 Fab has the most extensive available data. In the phase-III evaluation of 7E3 for the Prevention of Ischemic Complications trial, the administration of a c7E3 Fab bolus plus c7E3 Fab infusion reduced the rate of major ischaemic events by 35% at 30 days (p = 0.008) in patients undergoing high-risk PTCA. Major bleeding episodes occurred more frequently with this regimen than with placebo, although rates of intracranial haemorrhage or surgery for bleeding did not differ between groups. The findings suggest that the risk of bleeding complications might be reduced, without compromising efficacy, by administering heparin on a weight-adjusted basis in patients treated with c7E3 Fab.     

Correlation between clinical course and quantitative analysis of the ischemia related artery in patients with unstable angina pectoris, refractory to medical treatment. Results of two randomized trials. The European Cooperative Study Group

Patients with unstable angina, refractory to intensive medical therapy, are at high risk for developing thrombotic complications, such as recurrent ischemia, myocardial infarction and coronary occlusion during coronary angioplasty. As both platelet aggregation and/or thrombus formation play an important role in this ongoing ischemic process, a monoclonal platelet GPIIb/IIIa receptor antibody (c7E3) or thrombolytic therapy (alteplase) might be able to modify the clinical course and underlying coronary lesion morphology. To evaluate whether alteplase or c7E3 could influence the incidence of complications, we randomized 36 and 60 patients, respectively to alteplase or placebo, or c7E3 or placebo. All patients exhibited dynamic ECG changes and recurrent pain attacks, despite maximal tolerated medical therapy. Patients were randomized in both studies after initial angiography had demonstrated a culprit lesion amenable for angioplasty. After study drug infusion quantitative angiography was repeated and angioplasty performed. Recurrent ischemia during study drug infusion occurred in 5, 6, 9 and 16 patients from the alteplase, placebo, c7E3 and placebo group, respectively. Major events defined as death, myocardial infarction or urgent intervention occurred in 7, 3, 1 and 7 patients, respectively. Two patients died: one in the alteplase group and one in the placebo group from the c7E3 study. The first patient due to retroperitoneal hemorrhage, the second as a result of recurrent infarction. Qualitative angiography showed resolution of clots in the c7E3 group only, while the same group of patients showed in 20% an improvement in TIMI flow grade, without deterioration in any patient from this group.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Effects of beta3-integrin blockade (c7E3) on the response to angioplasty and intra-arterial stenting in atherosclerotic nonhuman primates

Because the beta3-antagonist abciximab (c7E3 Fab) has significantly improved late outcomes after coronary angioplasty, the beta3 integrins have been implicated in the arterial response to injury. However, the mechanisms underlying this benefit are unknown. The observation that c7E3 binds beta3 integrins on vascular cells (alphavbeta3) with affinity equal to that for the platelet glycoprotein IIb/IIIa integrin has led to the hypothesis that c7E3 may act directly on the artery wall to prevent restenosis after angioplasty. To test this hypothesis, we studied the effects of c7E3 on structural changes within the artery wall after angioplasty or stent angioplasty in 23 male cynomolgus monkeys with established atherosclerosis. Animals were randomly assigned to receive either a bolus of c7E3 (0.4 mg/kg IV, n=11) followed by a 48-hour infusion (0. 2 microg. kg-1. min-1) or an equal volume of vehicle (n=12). Animals received weight-adjusted aspirin and heparin and then underwent unilateral iliac artery experimental angioplasty and subclavian artery stent angioplasty (Palmaz). Iliac artery lumen diameter (LD) was determined by angiography at baseline (LDPre), after angioplasty (LDPost), and 35 days later (LDDay35). Arteries were then fixed by perfusion and removed for analysis. Lumen, intima, media, and external elastic lamina (EEL) areas were measured in iliac artery cross sections. Values from each injured iliac artery were normalized to the contralateral uninjured iliac artery to control for interanimal variability in baseline artery size and atherosclerosis extent. Intimal area was also measured in subclavian stent cross sections. c7E3 blocked platelet aggregation and prolonged the bleeding time from 2.8+/-1.1 to 19.8+/-2.5 minutes, P<0.001. Experimental angioplasty increased LDPost an average of 28%, and the initial gain was similar in both groups (P=NS). Despite an anti-platelet effect, c7E3 did not inhibit iliac lumen narrowing (LDDay35-LDPost: c7E3, -0.69+/-0.17 versus vehicle, -0.99+/-.17 mm, P=0.35); intimal hyperplasia (neointima area: c7E3, 1.12+/-.28 versus vehicle, 1.22+/-.20 mm2, P=0.77); or decrease in artery wall size (EEL area [percent of uninjured control]: c7E3, 101+/-7% versus vehicle, 121+/-7%). Stent intimal hyperplasia was also unaltered by c7E3 treatment (neointimal area: c7E3, 1.09+/-0.16 versus vehicle, 1. 28+/-0.11 mm2, P=0.36). These results suggest that the benefits of c7E3 treatment in coronary angioplasty were not from inhibition of intimal hyperplasia or improved artery wall remodeling. Alternative mechanisms should be explored to explain improved late outcomes after angioplasty in patients treated with c7E3.     

Long-term angiographic and clinical outcome of patients undergoing multivessel coronary stenting

BACKGROUND: Randomized clinical trials have shown that multivessel coronary angioplasty is feasible and provides similar long-term survival as bypass surgery in selected patients. However, the higher need for repeat intervention, in particular, coronary artery bypass graft surgery, remains a problem. The objective of this study was to test the hypothesis that multivessel stenting is safe and effective in reducing the need for repeat interventions, in particular, the need for bypass surgery. METHODS AND RESULTS: Between March 1993 and June 1995, 100 consecutive patients (243 lesions) had multivessel coronary stenting. High-pressure stent optimization was used in all patients. Procedural success was achieved in 97% of lesions; 2 patients (2%) required emergency bypass surgery. Angiographic follow-up was obtained in 89% of patients at 5.2+/-2.5 months. Angiographic restenosis occurred in 22% of the lesions, but 37% of patients had > or = 1 lesion with restenosis. Clinical follow-up was obtained in all patients at 21 +/- 10 months: target lesion revascularization was needed in 30 patients (30%), repeat angioplasty in 28 patients (28%) and coronary bypass surgery in 2 patients (2%); the overall survival rate was 96% (2% noncardiac death). CONCLUSIONS: Multivessel coronary stenting can be performed with high success rate and low need for emergency bypass surgery. Compared with historical results with multivessel percutaneous transluminal coronary angioplasty, patients who undergo multivessel stenting need less repeat interventions, in particular, less coronary bypass surgery and have similar long-term survival.     

Abciximab in primary coronary angioplasty for acute myocardial infarction improves short- and medium-term outcomes

OBJECTIVES: The purpose of this study was to compare the outcome of primary percutaneous transluminal coronary angioplasty for acute myocardial infarction (MI) when performed with or without the platelet glycoprotein IIb/IIIa antibody, abciximab. BACKGROUND: Abciximab improves the outcome of angioplasty but the effect of abciximab in primary angioplasty has not been investigated. METHODS: Data were collected from a computerized database. Follow-up was by telephone or review of outpatient or hospital readmission records. RESULTS: A total of 182 consecutive patients were included; 103 received abciximab and 79 did not. The procedural success rate was 95% in the two groups. At 30-day follow-up, the composite event rate of unstable angina, reinfarction, target vessel revascularization and death from all causes was 13.5% in the group of patients who did not receive abciximab, 4% (p < 0.05) in the abciximab group and 2.4% (p < 0.05) in the subgroup of patients (n = 87) who completed the 12-h abciximab infusion. At the end of follow-up (mean 7+/-4 months), the composite event rate was 32.4%, 17% (p < 0.05) and 13.1% (p < 0.01) in these three categories respectively. Abciximab bolus followed by a 12-h infusion was an independent predictor of event-free survival, in a Cox proportional hazards model (relative risk 0.49; 95% confidence interval 0.24 to 0.99; p < 0.05). CONCLUSIONS: Abciximab given at the time of primary angioplasty may improve the short- and medium-term outcome of patients with acute MI, especially when a 12-h infusion is completed.     

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.     

Reduction in complications of angioplasty with abciximab occurs largely independently of baseline lesion morphology. EPIC and EPILOG Investigators. Evaluation of 7E3 for the Prevention of Ischemic Complications. Evaluation of PTCA To Improve Long-term Outcome with abciximab GPIIb/IIIa Receptor Blockade

OBJECTIVES: We investigated the hypothesis that abciximab might lead to a differential effect among patients with different lesion morphologies; hence, its cost/benefit ratio would be optimized if it were used selectively on the basis of baseline angiographic findings. BACKGROUND: Major complications of coronary angioplasty occur in 4% to 9% of patients. In the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) and Evaluation of PTCA To Improve Long-term Outcome with abciximab GPIIb/IIIa Receptor Blockade (EPILOG) trials, abciximab decreased the ischemic complications after intervention by 35% to 56%. However, the cost of this agent is appreciable, and there remain concerns about the safety of its readministration. METHODS: There were 1,362 patients in EPIC and 2,792 patients in EPILOG randomized to either bolus plus an infusion of abciximab or placebo, administered with aspirin and heparin at the time of the coronary intervention. Data from these studies were combined, and a differential effect of abciximab in relation to baseline lesion morphology on 30-day risk of death, myocardial infarction or urgent intervention was investigated using the Breslow Day test for statistical interaction. RESULTS: Abciximab consistently reduced the relative risk of complications across all lesion morphologies studied, with the possible exception of patients treated with degenerated saphenous vein grafts (risk with placebo 16.3% vs. risk with abciximab 18.6%, Breslow Day test for interaction, p=0.08). However, the absolute reduction of risk was somewhat greater in patients with more complex B2 or C lesions (7.6% and 5.8%, respectively) than in patients with morphologically simpler A or B1 lesions (3.7% and 3.2%, respectively). CONCLUSIONS: The reduction of early adverse ischemic events associated with angioplasty by abciximab occurs largely independent of pretreatment morphology.     

Coronary angioplasty, a privileged method of myocardial revascularization of the elderly

Coronary angioplasty is a myocardial revascularisation technique of choice in the elderly, avoiding the need for general anesthesia as well as the complications of thoracotomy and extracorporeal circulation. Used in a continuous series of 62 patients, it provided a 79% primary success rate in this situation, where reaching the coronary artery and penetrating the stenosis may be difficult. Femoral complications (hematoma, false aneurysm) are commoner in this age group, but appear to be beneficially influenced by the replacement of heparin by ticlopidine peri-operatively. With 24 months follow-up, the proportion of patients free of any major cardiac event and NYHA classes I and II is 66%, actuarial survival rate without infarction is 76%. These results would tend to restrict the indications for bypass after the age of 75 to cases of stenosis of the left main coronary artery, failure of angioplasty or multi-vessel atheroma with a "culprit lesion" inaccessible to dilatation.     

Impact of diabetes mellitus on percutaneous revascularization (CAVEAT-I). CAVEAT-I Investigators. Coronary Angioplasty Versus Excisional Atherectomy Trial

We examined the relation between diabetes mellitus and outcomes in patients undergoing percutaneous coronary revascularization in the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT-I), a randomized trial comparing treatment with either percutaneous transluminal coronary angioplasty or directional atherectomy for de novo lesions in native coronary arteries. Acute success and complication rates, 6-month angiographic restenosis rates, and 1-year clinical outcomes were compared between diabetic and nondiabetic patients undergoing each procedure. Acute success rates between diabetic (n = 191) and nondiabetic (n = 821) patients were similar for both revascularization techniques. Except for the need for dialysis, complication rates were also similar. Six months after atherectomy, diabetic patients had significantly more angiographic restenosis than nondiabetics (59.7% vs 47.4%) and significantly smaller minimum luminal diameters (1.20 vs 1.40 mm). Diabetics undergoing atherectomy required more frequent bypass surgery (12.8% vs 8.5%) and more repeat percutaneous revascularizations (36.5% vs 28.1%) than nondiabetics undergoing atherectomy. Restenosis rates, minimum luminal diameters and repeat revascularizations between diabetics and nondiabetics undergoing angioplasty were similar. The higher restenosis and repeat revascularization rates and the smaller minimum luminal diameter at follow-up in diabetic patients suggest that atherectomy may provide only modest benefit for these patients. The increased restenosis rate in diabetics undergoing atherectomy (but not angioplasty) requires further evaluation.     

AMO array multifocal versus monofocal intraocular lenses: long-term follow-up

BACKGROUND: Reperfusion therapy by primary coronary angioplasty has been shown to be beneficial for patients who present themselves up to 12 h after the onset of symptoms. However, the relationship between outcome and ischaemic time for patients who present relatively late after the onset of symptoms is still uncertain. The aim of this study was to investigate differences in patient characteristics, left ventricular function and clinical outcome among early (< 3 h), intermediate (3-6 h) and late (6-24 h) treated patients. METHODS AND RESULTS: From August 1990 until December 1995, we studied 496 patients who underwent primary coronary angioplasty for acute myocardial infarction. Patients who underwent reperfusion therapy between 6 and 24 h were more often of female gender and more often had diabetes. Primary coronary angioplasty was less successful with later time to reperfusion. Patients who had reperfusion therapy within 6 h showed recovery of left ventricular function at 6 months follow-up, while the left ventricular function of patients treated late had deteriorated. Reocclusion of the infarct-related vessel at follow-up coronary angiography was highest for patients with an ischaemic time of more than 6 h. They more often suffered a repeat myocardial infarction and had a significantly higher 6 months mortality. After adjustment for age, heart rate at presentation, gender, and the presence of diabetes by multi-variate analysis, ischaemic time remained an independent predictor of both left ventricular function recovery and 6 month mortality. CONCLUSIONS: The time from symptom onset to reperfusion is related to some baseline clinical characteristics, procedural success rate, left ventricular function and clinical outcome.     

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.     

Expression of markers of platelet activation and the interpatient variation in response to abciximab

Our study concerns the biological effects of abciximab (c7E3 Fab, ReoPro), a powerful new antiplatelet drug that blocks glycoprotein (GP) IIb-IIIa complexes. Samples were examined from 6 patients with coronary artery disease who received a bolus of abciximab followed by a 10- microg/min infusion for at least 18 hours before percutaneous transluminal coronary angioplasty. Inhibition of ADP-induced PA was maximal for 4 patients but partial (79% and 53%) for 2 others during the infusion. Flow cytometry performed with monoclonal antibodies (PAC-1, AP-6, and F26) specific for the "activated" GP IIb-IIIa complex revealed large decreases in the expression of activation markers on platelets during therapy, but these decreases were less marked when inhibition of ADP-induced PA was incomplete. Residual aggregation was seen for all patients during the infusion when TRAP 14-mer peptide or thrombin was the stimulus. Unblocked GP IIb-IIIa complexes were detected on thrombin-stimulated platelets from the patients by immunoelectron microscopy performed using the monoclonal antibody AP-2. Unblocked GP IIb-IIIa complexes were also detected by flow cytometry when platelets preincubated for 1 hour in vitro with abciximab under saturating conditions were (1) incubated with TRAP 14-mer or (2) permeabilized with Triton X-100. In confirming interpatient variation in the platelet response to a standard dose of abciximab, our results also show that an uninhibited internal pool of GP IIb-IIIa complexes may mediate a residual response to strong agonists.     

Myocardial revascularisation in elderly patients with refractory or unstable angina and advanced coronary disease

BACKGROUND: Elderly patients with ischaemic heart disease are often treated more conservatively and for longer than younger patients, but this strategy may result in subsequent invasive intervention of more advanced and higher risk coronary disease. METHODS: We performed a retrospective analysis of 109 patients aged > or = 70 years (mean age 74 years, 66% men), who presented with angina refractory to maximal medical treatment or unstable angina over a 2-year period (1988-1990), to compare the relative risks and benefits of myocardial revascularisation [coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA)] in this higher-risk age group. RESULTS: Sixty patients underwent CABG and 49 patients PTCA. There were eight periprocedural deaths in total (six in the CABG group, and two in the PTCA group, P = 0.29). Six patients in the CABG group suffered a cerebrovascular accident (two fatal). Acute Q-wave myocardial infarction occurred in one patient in the CABG group and in two patients in the PTCA group. The length of hospital stay was longer for the CABG group (CABG group 11.4 +/- 5.4 days, range 7-30 days, PTCA group 7.4 +/- 7.6 days, range 1-39 days, P = 0.01). Outcome was assessed using the major cardiac event rate (MACE; i.e. the rate of death, myocardial infarction, repeat CABG or PTCA). The cumulative event-free survival in the CABG group in 1, 2 and 3 years was 87, 85 and 85%, respectively. In contrast, in the PTCA group it was 55, 48 and 48% (P = 0.0001). Age, sex, number of diseased vessels, degree of revascularisation and left ventricular function were not predictive of the recurrence of angina in both groups. Actuarial survival (total mortality, including perioperative mortality) was lower at 1 year in the CABG group due to the higher perioperative mortality, but similar in both groups after the second year (P = 0.62). CONCLUSIONS: Elderly patients with refractory or unstable angina who are revascularised surgically have a better long-term outcome (less frequent event rate of the composite end-point--myocardial infarction, revascularisation procedures and death) compared with those who are revascularised with PTCA. This benefit is been realised after the second year. Total mortality is similar in both groups after the second year. Therefore elderly patients who are fit for surgery should not be denied the benefits of CABG. PTCA may be regarded as a complementary and satisfactory treatment, especially for those whose life expectancy is limited to less than 2 years. The use of stents may improve outcome in the PTCA group and this needs to be evaluated.     

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.     

Modifiable risk factors for vascular access site complications in the IMPACT II Trial of angioplasty with versus without eptifibatide. Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis

OBJECTIVES: This study was designed to identify potential predictors of vascular access site (VAS) complications in the large-scale Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT) II trial, which studied angioplasty with versus without a new glycoprotein (GP) IIb/IIIa receptor inhibitor (eptifibatide). BACKGROUND: GP IIb/IIIa receptor inhibition during coronary interventions has been associated with excess VAS complications. If other predictors of VAS complications could be identified, they might be manipulated to reduce complications. METHODS: A total of 4,010 patients undergoing percutaneous transluminal coronary revascularization (PTCR) were randomized into one of three bolus/20- to 24-h infusion arms: placebo bolus/placebo infusion; 135-microg/kg body weight eptifibatide bolus/0.5-microg/kg per min eptifibatide infusion; or 135-microg/kg eptifibatide bolus/0.75-microg/kg per min eptifibatide infusion. Heparin during the procedure was weight adjusted and stopped 4 h before sheaths were removed. Logistic regression modeling was used to identify independent predictors of VAS complications. RESULTS: VAS complications were more common in patients treated with eptifibatide (9.9% vs. 5.9% placebo-treated patients, p < 0.001). Multivariate analysis identified eptifibatide therapy (p < 0.0001), advanced age (p = 0.0001), longer time to sheath removal (p = 0.0002), stent placement (with intense post-stent anticoagulation) (p = 0.0004), female gender (p = 0.0006), PTCR within 24 h of thrombolytic therapy (p = 0.002), larger heparin doses during PTCR (p = 0.009), major coronary dissection (p = 0.03) and placement of a venous sheath (p = 0.04) as independent predictors of VAS complications. CONCLUSIONS: VAS complications may be reduced by early sheath removal, by avoiding placement of venous sheaths and by limiting heparin dosing to avoid excessive activated clotting times. Early sheath removal during inhibition of platelet aggregation by eptifibatide is feasible.     

Management of patients with unstable angina in a general cardiology unit

AIMS: To review the clinical management of patients with unstable angina and to relate prospectively initial risk stratification, according to the Braunwald criteria, to subsequent cardiovascular events. METHODS: From February to April 1996 we performed a three month prospective review of all patients with a diagnosis of unstable angina admitted to the coronary care unit at Auckland Hospital. RESULTS: One hundred and four patients (61% male), with a mean age of 64 years, were classified as high (58%), intermediate (41%) or low risk (1%) for an adverse cardiac event. Twelve (12%) patients had a documented myocardial infarction, of whom 11 were in the high-risk group (p = 0.038). During hospitalisation there was one death. Twelve (12%) patients underwent inpatient exercise testing, five of whom proceeded to a coronary angiogram prior to hospital discharge. Twenty-two (21%) unstable patients underwent inpatient angiography without prior exercise testing. Twenty-one (20%) patients required revascularisation on the same admission: percutaneous coronary angioplasty (n = 14) or coronary artery bypass grafting (n = 7). Twelve of these 21 patients were in the high-risk group (p = 0.999, NS). CONCLUSION: Patients admitted with unstable angina had low inpatient mortality but a 12% rate of subsequent myocardial infarction. Braunwald low-risk unstable angina patients were not admitted to the coronary care unit. Braunwald high-risk patients were more likely to develop a subsequent myocardial infarction. Stratification of patients into intermediate or high-risk groups did not relate to initial medical management or subsequent revascularisation. Thus, while this method of risk stratification may predict cardiovascular events, it may be of limited clinical use in the New Zealand environment.     

Effect of nadroparin, a low-molecular-weight heparin, on clinical and angiographic restenosis after coronary balloon angioplasty: the FACT study. Fraxiparine Angioplastie Coronaire Transluminale

BACKGROUND: Experimental studies suggest that the antiproliferative effect of heparin after arterial injury is maximized by pretreatment. No previous studies of restenosis have used a pretreatment strategy. We designed this study to determine whether treatment with nadroparin, a low-molecular-weight heparin, started 3 days before the procedure and continued for 3 months, affected angiographic restenosis or clinical outcome after coronary angioplasty. METHODS AND RESULTS: In a prospective multicenter, double-blind, randomized trial, elective coronary angioplasty was performed on 354 patients who were treated with daily subcutaneous nadroparin (0.6 mL of 10,250 anti-Xa IU/mL) or placebo injections started 3 days before angioplasty and continued for 3 months. Angiography was performed just before and immediately after angioplasty and at follow-up. The primary study end point was angiographic restenosis, assessed by quantitative coronary angiography 3 months after balloon angioplasty. Clinical follow-up was continued up to 6 months. Clinical and procedural variables and the occurrence of periprocedural complications did not differ between groups. At angiographic follow-up, the mean minimal lumen diameter and the mean residual stenosis in the nadroparin group (1.37+/-0.66 mm, 51.9+/-21.0%) did not differ from the corresponding values in the control group (1.48+/-0.59 mm, 48.8+/-18.9%). Combined major cardiac-related clinical events (death, myocardial infarction, target lesion revascularization) did not differ between groups (30.3% versus 29.6%). CONCLUSIONS: Pretreatment with the low-molecular-weight heparin nadroparin continued for 3 months after balloon angioplasty had no beneficial effect on angiographic restenosis or on adverse clinical outcomes.     

Is the stress test useful in the detection of post-angioplasty restenosis?

Restetenosis is still the greatest limitation of coronary angioplasty (PTCA). The systematic use of ergometry (PE) with the objective of identifying restenosis is controversial and, namely, the ACC/AHA does not recommend its routine use. Our objective was to conduct a retrospective study of the use of PE when performed late (3 to 6 months) for the detection of restenosis. As a protocol, our group performed "late" PE on all the patients without contraindications, the patients with positive ergometry or CCS class II-IV angor submitted to angiographic control. Between January 1996 and July 1997, 121 patients (pts) were submitted to PTCA. Our study population was composed of patients submitted to complete revascularisation with follow-up in our centre: 59 pts (49%) with an average age of 58 +/- 12 years, 82% male. Eighty-three percent of the pts had revascularisation in a context of unstable angina, 10% in the acute phase of myocardial infarction and 7% due to chronic angina. Stents were implanted in 42% of the pts. In the follow-up after six months, 7 pts complained of CCS class II or III angor. The ergometry showed positive electrocardiographic criteria in 11 pts (18.6%). All pts with angor had positive PE. All these pts were submitted to angiographic control; restenosis (residual stenosis equal to or above 50%) was observed in all the patients who complained of angor (100% positive predictive value); restenosis occurred in 9 pts with positive ergometry (82% positive predictive value). In asymptomatic pts, PE indicated 2 pts with restenosis (2/59-3.4%) and two false positive (2/11-18%). At six months, PE detected 22% of the pts with restenosis. In conclusion, complete post-revascularisation angor due to coronary angioplasty has a higher positive predictive value than ergometry. However, the stress test, performed systematically, can identify an additional percentage of pts with restenosis with an acceptable percentage of false positives.     

Incidence and prognosis of early primary cardiogenic shock in myocardial infarction

The aim of this retrospective study was to analyse the results of coronary reperfusion on the incidence and short and medium term prognosis of early primary cardiogenic shock in acute myocardial infarction. Of 339 consecutive patients admitted within 6 hours of the onset of acute myocardial infarction, 25 (7.4%) had cardiogenic shock from the onset. The majority of patients (18) underwent direct angioplasty with a successful result in 16 cases. Intravenous thrombolysis was instituted in 5 cases followed by emergency coronary angiography leading to "rescue" coronary angioplasty in 3 cases, which was successful in 2 cases. Two patients had no coronary revascularisation because of a double contra-indication to thrombolysis and catheterization by the femoral approach. Intra-aortic balloon pumping was used in 17 cases. Complementary emergency surgical revascularization was necessary in 5 patients (20%). In all, early reperfusion of the infarct-related artery was obtained in 80% of cases (20 patients). The hospital mortality was 72% (18 patients) due to refractory cardiac failure in nearly all cases. After an average follow-up of 17 months, 3 of the 7 survivors of the hospital period have died and of the 4 remaining patients, 2 are in the NYHA classes III or IV. Recent therapeutic advances have not influenced the incidence of cardiogenic shock but have significantly increased the proportion of very early cardiogenic shock, whereas the late cardiogenic shocks of more progressive onset, have nearly disappeared (4/339, 1.2% in this series). The prognosis of these early shocks, caused by severe myocardial damage, remains catastrophic and hardly improved by emergency coronary reperfusion by angioplasty and intraaortic balloon pumping.(ABSTRACT TRUNCATED AT 250 WORDS)