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Thrombolysis has become an accepted form of therapy for acute myocardial infarction. As demonstrated in the Global Utilization of Streptokinase and t-PA for Occluded Arteries trial, early, complete and sustained patency of the infarctrelated coronary artery is correlated with reduced mortality. However, current thrombolytic regimens are able to achieve such patency within 90 min in only 81% of cases. To improve the risk/benefit ratio of thrombolytic therapy, newer agents such as reteplase have been developed to establish more rapid, more complete and more stable coronary artery patency, thus reducing mortality.This report summarizes the pharmacological properties of reteplase. It also summarizes the findings from various animal and clinical studies in which reteplase was compared with alteplase and streptokinase and the findings from animal and clinical studies evaluating infusion, single-bolus, and double-bolus doses of reteplase. [ABSTRACT FROM PUBLISHER]

Thrombolytic therapy has been recognized as a significant improvement in the management of acute myocardial infarction. Thrombolytic agents however have been limited by short half-lives that necessitate complex administration protocols and by the potential for bleeding complications.The native t-PA molecule has since been modified in an attempt to achieve improved lytic characteristics with less risk of bleeding.Reteplase is a third-generation recombinant mutant of tissue-type plasminogen activator (t-PA) that is expressed in Escherichia coli cells and consists of the kringle 2 and the protease domains of t-PA. Compared with t-PA, reteplase has a lower fibrin binding, which may translate to improved clot penetration. As well as a longer half-life and a more rapid initiation of thrombolysis. Preclinical pharmacology studies have indicated that reteplase has potent in vivo thrombolytic activity and leads to rapid reperfusion; these findings have been confirmed by promising results obtained in large-scale clinical trials.Other new agents developed by modifying the native t-PA molecule include the n-PA and the TNK mutants of t-PA. These novel, genetically modified thrombolytic agents all lyse clots better than the native t-PA; however, they differ with respect to their half-lives and fibrin-binding activity.Although all the third-generation thrombolytic agents have shown considerable potential in improving the efficacy of thrombolytic therapy, their risk of intracranial bleeding remains problematic and is still somewhat uncertain. [ABSTRACT FROM PUBLISHER]

The ability of thrombolytic therapy to lower mortality in patients with acute myocardial infarction was first demonstrated in 1986 by the Gruppo Italiano per lo Studio della Streptochinasi nell'lnfarto Miocardico. In the ensuing 10 years, large efforts have been undertaken to develop more effective and safer thrombolytic agents. In addition, the value of adjunctive agents influencing thrombotic and thrombolytic processes was demonstrated, and newer agents are under active investigation. This review focuses on theoretical and practical aspects of optimizing thrombolytic therapy and on genetically engineered third generation plasminogen activators. Optimized thrombolytic therapy may make this form of therapy available to patients who are currently considered ineligible, and it will lead to earlier, more complete reperfusion of infarct-related coronary arteries. The benefits and risks of optimized thrombolytic regimens relative to those of mechanical reperfusion strat egies will require constant reassessment while both forms of treatment develop. [ABSTRACT FROM PUBLISHER]

Ultrasound transducer-tipped guidewires can be used for coronary interventions, and they permit the monitoring of coronary flow before during, and after the interventions. The flow signal contains valuable information regarding the quality and stability of the final result. Restoration of typical phasic flow patterns with diastolic predominance is one guide to final result. Monitoring the trend in average velocity over several minutes after completion of the procedure can detect subtle alterations in flow that may presage abrupt closure. These flow alterations might also help predict active plaques with heavy thrombus involvement that may undergo recurrence in the weeks and months after successful procedures. [ABSTRACT FROM PUBLISHER]

Intracoronary streptokinase administration during acute myocardial infarction is a time-consuming and potentially dangerous technique. However, it does appear to be beneficial in terms of reduced mortality and improved left ventricular function. We have prospectively studied 258 patients with acute myocardial infarction of whom 180 were subjected to acute cardiac catheterisation and intracoronary streptokinase administration. The remaining 78 either refused the protocol or met exclusion criteria and were studied prospectively as a control group. Patients with anterior myocardial infarction demonstrated a most profound improvement in both mortality and myocardial function with intracoronary thrombolytic therapy. Patients with inferior myocardial infarction demonstrated an improvement in left ventricular function with successful coronary reperfusion, but did not achieve a statistically significant improvement in mortality compared to controls. Time from onset of pain to reperfusion up to 18 h after onset of pain did not affect improvement in left ventricular function or survival. Patients more than 65 years of age did not show a difference in survival when treated with thrombolytic therapy compared with controls of similar age group. However, patients less than 65 years of age treated with intracoronary streptokinase therapy demonstrated a mortality of 4% compared to 18% in similar controls. Two patients may have died as a direct result of intracoronary thrombolytic therapy, but no patients died as a result of bleeding complications. Thus, the most striking results with intracoronary thrombolytic therapy during evolving myocardial infarction are seen in patients with anterior myocardial who are less than 65 years of age. Time from onset of pain to reperfusion and presence of Q waves on initial electrocardiogram do not affect the observed outcome of this intervention. [ABSTRACT FROM PUBLISHER]

Changes in skin resistance and beat-by-beat heart rate, derived from the EKG, were obtained from the same pair of dry silver electrodes applied to the finger tips. The electronic criteria to be satisfied for application of this technique are discussed. The recording system was constructed using low-cost, solid-state circuitry. A typical record of changes in skin resistance and beat-by-beat heart rate is presented to demonstrate the performance characteristics of the equipment. [ABSTRACT FROM AUTHOR]

Coronary guidewires with ultrasound transducer tips are commercially available and are appropriately sized for use in coronary interventions. These guidewires permit monitoring of coronary flow before, during and after the interventions. The measured flow signal contains valuable information regarding the quality and the stability of the final result. After completion of the procedure, monitoring the trend in average velocity over several minutes can reveal subtle alterations in flow that may presage abrupt closure. Abnormal or unstable flow patterns also may help predict lesions that might develop recurrences in the weeks and months after successful procedures. [ABSTRACT FROM PUBLISHER]

Acute reintervention was performed in 26 of 1,620 patients after coronary stenting (1.6%). Half of the patients had stent thrombosis and the other half residual anatomic problems. The mean time for reintervention was shorter in patients with stent thrombosis. All patients with stent thrombosis had a sudden recurrence of chest pain. Electrocardiographic changes were more common with stent thrombosis. Composite end point occurred in 10 patients (77%) with stent thrombosis versus 5 (39%) in the other group (p = 0.04). [ABSTRACT FROM AUTHOR]

The percutaneous Hemopump showed beneficial effects during coronary angioplasty in 32 high-risk patients with unloading of the left ventricle during ischemia and maintaining cardiac output with mean aortic pressures of 50 mm Hg in case of cardiac arrest (3 patients). High procedure-related morbidity (occlusion of femoral artery in 2 patients; bleeding with need of transfusion in 4 patients) and mortality (4 of 32 patients) rates demonstrate the need for a very careful selection of patients. [ABSTRACT FROM AUTHOR]

Slow or no-reflow phenomenon (SNR) complicates 10%-15% of cases of percutaneous intervention (PCI) in aortocoronary saphenous vein grafts (SVG). At present, there are no uniform, effective strategies to predict or prevent this common and potentially serious complication. The purpose of our study was to characterize variables correlated with the risk of SNR in SVG PCI in the era of stenting and glycoprotein IIb/IIIa receptor inhibitors. We identified 2,898 consecutive patients who had PCI, of whom 163 underwent PCI of at least one SVG. The clinical and angiographic characteristics of patients who developed SNR (SNR group) were compared with those who did not (no-SNR group). A total of 23 patients experienced SNR and 140 did not. Using a stepwise multivariate logistic regression analysis, four independent predictors for SNR were detected: probable thrombus (OR 6.9; 95% CI, 2.1-23.9; P = 0.001), acute coronary syndromes (OR 6.4; 95% CI, 2.0-25.3; P = 0.003), degenerated vein graft (OR 5.2; 95% CI, 1.7-16.6; P = 0.003), and ulcer (OR 3.4; 95% CI, 0.99-11.6; P = 0.04). The risk of developing SNR could be estimated according to the number of predictors found: low-grade risk (1%-10%) if < or = one variable was present, moderate risk (20%-40%) if two variables were present, and high risk (60%-90%) if three or more variables were present. We identified and quantified current risk factors for SNR and concluded that the risk of developing SNR during PCI in SVG can be predicted by simple clinical and angiographic variables obtained before PCI. This information may be useful when the risk of PCI has to be balanced against alternative strategies such as medical therapy or redo-bypass surgery or in the selection of those patients that will most benefit from the use of protection devices during PCI., (Copyright 2001 Wiley-Liss, Inc.)

Background: The histological appearance of stenosis in de novo saphenous venous grafts (DNSVG) consists of diffuse atherosclerosis that contains blood elements, necrotic debris and limited fibrocollagenous tissue. The friable nature of these lesions complicates percutaneous intervention (PCI) procedures. On the other hand, in-stent restenosis (ISR) of SVG is due primarily to atherosclerotic plaque or fibromuscular hyperplasia, with thrombus formation playing a secondary role. The purpose of this study is to compare the results of PCI in these two types of SVG lesions., Methods: We reviewed our institutional interventional database from March 1996 through February 2000 and identified all consecutive patients who underwent PCI of at least one SVG. One hundred and ten patients were identified: 89 undergoing DNSVG intervention and 21 patients with ISR lesions., Results: Acute coronary syndromes, degenerated and thrombus-containing lesions were more common in the DNSVG group. "Slow-, no-reflow" complicated 20% of the DNSVG lesions compared to none of the ISR lesions (p = 0.02). Post-procedural myocardial infarction was higher in the DNSVG group (13.5% versus 0%; p = 0.1) and correlated significantly with the occurrence of "slow-, no-reflow" (r = 0.43; p = 0.0001). Utilizing statistical modeling to adjust for baseline differences between the groups, ISR lesions were associated with a low risk of procedural complications (r = 0.22; p = 0.03)., Conclusion: This study demonstrates that in this relatively high-risk population, PCI is safer in ISR lesions than in de novo SVG lesions.

Various surgical options for internal carotid or subclavian artery pseudoaneurysm repair have been reported; however, in general they have resulted in poor outcomes with high morbidity and mortality rates. Recently, these open surgical procedures have been partly replaced by percutaneous transluminal placement of endovascular devices. We evaluated the potential for using flexible self-expanding uncovered stents with or without coiling to treat extracranial internal carotid, subclavian and other peripheral artery posttraumatic pseudoaneurysm. Three patients with posttraumatic pseudoaneurysm were treated by stent deployment and coiling (two cases) of the aneurysm cavity. In one case, a 5.0 x 47 mm Wallstent (Boston Scientific) was positioned to span the neck of the 9 x 5 mm size pseudoaneurysm (left internal carotid artery) and deployed. Angiography demonstrated complete occlusion of the pseudoaneurysm without coiling. In the second patient, a 5.0 x 31 mm Wallstent (Boston Scientific) was positioned to span the neck of the 9 x 7 mm size pseudoaneurysm (right internal carotid artery) and deployed. A total of six coils (Guglielmi Detachable Coils, Boston Scientific) were deployed into the pseudoaneurysm cavity until it was completely obliterated. In the third case, an 8.0 x 80 mm SMART (Cordis) stent was advanced over the wire, positioned to span the neck of the 10 x 7 mm size pseudoaneurysm of the left subclavian artery, and deployed. Fourteen 40 x 0.5 mm Trufill (Cordis) pushable coils were deployed into the pseudoaneurysm cavity until it was completely obliterated. At long-term follow-up (6-9 months), all patients were asymptomatic without flow into the aneurysm cavity by Duplex ultrasound. We conclude that uncovered endovascular flexible self-expanding stent placement with transstent coil embolization of the pseudoaneurysm cavity is a promising new technique to treat posttraumatic pseudoaneurysm vascular disease by minimally invasive methods, while preserving the patency of the vessel and side branches.

Objective: We examined long-term outcomes of patients with in-stent restenosis (ISR) who underwent different percutaneous interventions at the discretion of individual operators: balloon angioplasty (BA), repeat stent or rotational atherectomy (RA). We also examined long-term outcomes of patients with ISR who underwent coronary artery bypass surgery (CABG)., Background: In-stent restenosis remains a challenging problem, and its optimal management is still unknown., Methods: Symptomatic patients (n = 510) with ISR were identified using cardiac catheterization laboratory data. Management for ISR included BA (169 patients), repeat stenting (117 patients), RA (107 patients) or CABG (117 patients). Clinical outcome events of interest included death, myocardial infarction, target vessel revascularization (TVR) and a combined end point of these major adverse cardiovascular events (MACE). Mean follow-up was 19+/-12 months (range = 6 to 61 months)., Results: Patients with ISR treated with repeat stent had significantly larger average post-procedure minimal lumen diameter compared with BA or RA (3.3+/-0.4 mm vs. 3.0+/-0.4 vs. 2.9+/-0.5, respectively, p < 0.05). Incidence of TVR and MACE were similar in the BA, stent and RA groups (39%, 40%, 33% for TVR and 43%, 40%, 33% for MACE, p = NS). Patients with diabetes who underwent RA had similar outcomes as patients without diabetes, while patients with diabetes who underwent BA or stent had worse outcomes than patients without diabetes. Patients who underwent CABG for ISR, mainly because of the presence of multivessel disease, had significantly better outcomes than any percutaneous treatment (8% for TVR and 23% for MACE)., Conclusions: In this large cohort of patients with ISR and in the subset of patients without diabetes, long-term outcomes were similar in the BA, repeat stent and RA groups. Tissue debulking with RA yielded better results only in diabetic patients. Bypass surgery for patients with multivessel disease and ISR provided the best outcomes.

We describe a case of type 2 coronary artery perforation in a 73-year-old man undergoing coronary artery rotablation and stenting with abciximab therapy. The coronary artery perforation was successfully treated by coil embolization with Trufill pushable coils made from platinum alloy and synthetic fibers to promote maximum thrombogenicity.

Slow or no reflow (SNR) complicates 10-15% of cases of percutaneous intervention (PI) in saphenous vein bypass graft (SVG). To date there have been limited options for the prevention and treatment of this common and potentially serious complication. We evaluated the procedural outcome of 143 consecutive SVG interventions. We compared patients who received pre-intervention intra-graft adenosine boluses with those who did not. In addition we examined the efficacy of adenosine boluses to reverse slow-no reflow events. Angiograms were reviewed and flow graded (TIMI grade) by film readers blinded to the use of any intraprocedural drug or clinical history. Seventy patients received intragraft adenosine boluses before percutaneous intervention (APPI), 73 received no preintervention adenosine (NoAPPI). There were no significant angiographic differences between the two groups at baseline. A total of 20 patients experienced SNR. The incidence of SNR was similar in the two groups (APPI = 14.2% vs. NoAPPI = 13.6%, P = 0.9). SNR was treated with repeated, rapid boluses (24 microg each) of intra-graft adenosine. Reversal of SNR was observed in 10 of 11 patients (91%) who received high doses of adenosine (>/=5 boluses, mean 7.7 +/- 2.6) and in 3 of 9 (33%) of those who received low doses (<5 boluses, mean 1.5 +/- 1.2). Final TIMI flow was significantly better in the high dose than in the low dose group (final TIMI 2.7 +/- 0.6 vs. 2 +/- 0.8, P = 0.04). No significant untoward complications were observed during adenosine infusion. These findings suggest that SNR after PI in SVG is not prevented by pre-intervention adenosine, but it can be safely and effectively reversed by delivery of multiple, rapid and repeated boluses of 24 microg of intra-graft adenosine.

Percutaneous intervention in acute myocardial infarction has been associated with a high incidence of "no reflow," ranging from 11% to 30%, with an increased risk of complications. The role of intracoronary adenosine for the prevention of this phenomenon has not been evaluated fully. We studied the procedural outcomes of 79 patients who underwent percutaneous intervention in the context of acute myocardial infarction. Twenty-eight patients received no intracoronary adenosine, and 51 received intracoronary adenosine boluses (24-48 microg before and after each balloon inflation). Eight patients who were not given adenosine experienced no reflow (28.6%) and higher rates of in-hospital death, while only three of 51 patients (5.9%; P = 0.014) in the adenosine group experienced no reflow. No untoward complications were noted during adenosine infusion. Intracoronary adenosine bolus administration during percutaneous intervention in the context of acute myocardial infarction is easy and safe and may significantly lessen the incidence of no reflow, which may improve the outcome of this procedure.

Background: Acute and subacute stent thromboses (ASST) are the major thrombotic complications of coronary stenting. The time course of ASST seems to be related to the type of antithrombotic therapy (four days in patients treated with aspirin and coumadin compared to 12 hours with the use of aspirin and ticlopidine). In this report, we compared the timing of ASST in patients treated with aspirin, ticlopidine/clopidogrel, heparin and tirofiban with that in patients treated with the same drugs but without tirofiban., Methods: Retrospective analysis of the Hermann intervention database between January 1997 and October 1999 was performed. We identified 13 patients who required reintervention in the first week after a successful coronary stenting ( 1 stent). Four patients were treated with tirofiban (Group 1) and 9 were not (Group 2)., Results: The median time from stent deployment to ASST was 7 hours (interquartile range, 2.5Eth 33 hours) in group 2 compared to 84.5 hours (interquartile range, 56Eth 124.5 hours) in group 1. The mean time from stent deployment to ASST was 90.3 +/- 43.1 hours in group 1 versus 12.8 +/- 15.3 hours in group 2 (p = 0.0005). All episodes of ASST occurred 3 days in patients treated with tirofiban, whereas they occurred in the first 2 days in all patients not treated with tirofiban., Conclusion: Prophylactic tirofiban treatment delays the time to stent thrombosis after successful coronary artery stent implantation for more than two days. Patients at high risk for stent thrombosis treated with short-acting glycoprotein IIb/IIIa platelet receptor inhibitors may warrant close follow-up during the first week after stenting.

Positioning of the transseptal needle during percutaneous transvenous mitral commissurotomy (PTMV) can become a difficult and risky procedure when distortion of the interatrial septum exists. We present two cases where intracardiac echocardiography (ICE) facilitated the transseptal puncture in the presence of bulging of the fossa ovalis into the right atrium.

Rotational atherectomy (RA) of complex, calcified lesions has been associated with a high incidence of no reflow ranging from 6%-15% and concomitant myocardial necrosis with adverse prognostic implications. There are no uniform strategies for preventing this complication. The role of intracoronary adenosine for the prevention of this phenomenon during RA has not been fully evaluated. We studied the procedural outcome of 122 patients who underwent RA of complex native coronary artery lesions. Fifty-two patients received no adenosine but a variety of other agents. Seventy patients received intracoronary adenosine boluses (24 to 48 microgram prior to and after each RA run). There was no difference in the type of lesion studied, run time, or Burr to artery ratio (0.6-0.7) between the two groups. Six patients without adenosine experienced no reflow (11.6%), with resultant infarction in the target artery territory, while only 1 of 70 patients (1.4%, P - 0.023) in the adenosine group experienced no reflow. No untoward complications were observed during adenosine infusion. Intracoronary adenosine bolus administered during rotational atherectomy is easy, safe, and may significantly reduce the incidence of no reflow, which may improve the 30-day outcome of this procedure., (Copyright 1999 Wiley-Liss, Inc.)

Primary stenting for acute MI has been shown to be an improvement over PTCA alone. As with primary PTCA however there is an obligate delay in restoration of TIMI flow due to the time necessary for mobilization of the cath lab team. It is possible that a hybrid approach using partial thrombolysis plus early IIB/IIIA inhibitor administration followed by urgent angiography and stenting of the culprit lesion will be the ideal approach.

Background: Lanoteplase (nPA) is a rationally designed variant of tissue plasminogen activator with greater fibrinolytic potency and slower plasma clearance than alteplase., Methods and Results: InTIME (Intravenous nPA for Treatment of Infarcting Myocardium Early), a multicenter, double-blind, randomized, double-placebo angiographic trial, evaluated the dose-response relationship and safety of single-bolus, weight-adjusted lanoteplase. Patients (n=602) presenting within 6 hours of acute myocardial infarction were randomized and treated with either a single-bolus injection of lanoteplase (15, 30, 60, or 120 kU/kg) or accelerated alteplase. The primary objective was to determine TIMI grade flow at 60 minutes. Angiographic assessments were also performed at 90 minutes and on days 3 to 5. Follow-up was continued for 30 days. Lanoteplase achieved its primary objective, demonstrating a dose-response in TIMI grade 3 flow at 60 minutes (23.6% to 47.1% of subjects, P<0. 001). Similar results were observed at 90 minutes (26.1% to 57.1%, P<0.001). At 90 minutes, coronary patency (TIMI 2 or 3) increased across the dose range up to 83% of subjects at 120 kU/kg lanoteplase compared with 71.4% with alteplase. Thus, at this dose, lanoteplase was superior to alteplase in restoring coronary patency (difference, 12%; 95% CI, 1% to 23%). The early safety experience in this study suggests that lanoteplase was well tolerated at all doses with safety comparable to that of alteplase., Conclusions: Lanoteplase, a single-bolus, weight-adjusted agent, increased coronary patency at 60 and 90 minutes in a dose-dependent fashion. Coronary patency at 90 minutes was achieved more frequently with 120 kU/kg lanoteplase than alteplase. In this study, safety with lanoteplase and alteplase was comparable. InTIME-II, a worldwide mortality trial, will evaluate efficacy and safety with this promising new agent.

The molecular pharmacology of plasminogen activators and its implications for thrombolytic therapy are discussed. The benefits of coronary thrombolysis were first demonstrated with intracoronary and i.v. streptokinase. Tissue plasminogen activator (t-PA) or recombinant t-PA (alteplase) proved to be superior to streptokinase with respect to speed of reperfusion and reperfusion efficacy. Since alteplase neither lessened the risk of bleeding found with streptokinase nor generated Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow rates above about 50%, the quest for faster-acting, safer, and more effective thrombolytic agents has continued. The ideal agent would be highly efficient at converting plasminogen to plasmin, have an intermediate half-life, have a low affinity for fibrin, and be of reasonable cost. Genetic engineering of the wild-type t-PA molecule resulted in reteplase, which has a longer half-life than alteplase and may be superior in terms of lytic activity, myocardial salvage, and survival. Also under investigation are TNK-t-PA and n-PA, which have longer half-lives and, in animal models, seem to produce more rapid and complete thrombolysis, at less risk of intracranial bleeding, than alteplase. The risk of intracranial bleeding remains a problem with all thrombolytics; the risk versus the benefit will have to be assessed in large randomized trials. An understanding of the functions of various regions of the t-PA molecule has led to genetic engineering of new and promising plasminogen activators.

Objectives: This study sought to determine whether infrapopliteal transcatheter interventions can salvage ischemic limbs in diabetic patients referred for below the knee amputation at our institution., Background: The value of transcatheter interventions in diabetic crural arteries is controversial. Tissue oxygen partial pressure (TCO2) levels < 40 mm Hg predict poor wound healing., Methods: Percutaneous interventions were performed in 29 consecutive diabetic patients in need of limb salvage. Technical success was defined as < 20% residual vessel stenosis. Clinical success was defined as the avoidance of amputation and achievement of wound healing. At hospital discharge, patients were treated with Coumadin and aspirin. Ankle-brachial index (ABI) and TCO2 measurements were obtained before and after the intervention., Results: After 12-month follow-up, six patients had presistent wounds, whereas 23 experienced wound healing. Forty of the 50 infrapopliteal arteries successfully dilated were occluded, with a mean (+/-SD) lesion length of 18.0 +/- 3.5 cm. After the procedure, TCO2 improved from 27.82 +/- 9.97 mm Hg (95% confidence interval [CI] 23.95 to 31.69) to 54.5 +/- 14.73 mm Hg (95% CI 48.79 to 60.21, p < 0.0001), whereas the ABI did not (p > 0.2). TCO2 predicted procedural and clinical success (p < 0.0182)., Conclusions: Infrapopliteal transcatheter interventions in diabetic patients may salvage the majority of limbs doomed to amputation. Although TCO2 measurements are valuable in predicting wound healing and success after interventions, ABI measurements are not.

Reteplase (r-PA) is a genetically engineered deletion mutant of wild-type tissue-type plasminogen activator. The structural differences lead to different functional properties, such as a prolonged half-life. The compound demonstrated good thrombolytic efficacy in in vitro as well as in animal studies. In angiographically controlled patency studies (GRECO, GRECO-2 RAPID-1, RAPID-2), the double-bolus application scheme was established, and a superior patency profile for reteplase in comparison to alteplase was demonstrated. Mortality studies established reteplase as a safe drug with a 30-day mortality at least equivalent to streptokinase (INJECT) and very similar to alteplase (GUSTO-3). A possible advantage may be the double-bolus application without a need for weight adjustment, especially in a prehospital setting. Thus, reteplase can be regarded as an excellent alternative to streptokinase or alteplase for thrombolytic therapy in acute myocardial infarction.

Thrombolytic therapy has been shown to reduce mortality and morbidity after acute myocardial infarction. Therapeutic benefit seems to be directly correlated with completeness of reperfusion (Thrombolysis in Myocardial Infarction [TIMI] grade 3 flow) of the infarct-related coronary artery, as well as the timeliness of reperfusion. To determine which regimen of reteplase (r-PA), a deletion mutant of wild-type tissue plasminogen activator (t-PA), is most effective for clinical thrombolysis, several reteplase regimens were compared with the most successful standard regimens of recombinant t-PA (alteplase) in 2 large-scale, randomized studies. All patients received aspirin and intravenous heparin. In the Reteplase Angiographic Phase II International Dose Finding Trial (RAPID-1), results in 606 randomized patients showed that a 10 + 10 U double bolus of reteplase was more effective than a 15 U single bolus, a 10 + 5 double bolus, or conventional alteplase (100 mg over 3 hours). In the Reteplase versus Alteplase Patency Investigation During Acute Myocardial Infarction (RAPID-2) trial, results in 324 patients showed that significantly more patients achieved patency of the infarct-related artery (TIMI grade 2 or 3 flow) at 90 minutes with reteplase (10 + 10 U double bolus) than with accelerated alteplase (100 mg over 90 minutes): 83.4% versus 73.3%, respectively (p = 0.03). The incidence of complete patency (TIMI grade 3 flow) at 90 minutes was likewise greater with reteplase than with accelerated alteplase (59.9% vs 45.2%, respectively; p = 0.01). At 60 minutes, the incidence of TIMI grade 2 or 3 flow was also significantly higher with reteplase than with alteplase (81.8% vs 66.1%, respectively; p = 0.01), as was the incidence of TIMI grade 3 flow (51.2% vs 37.4%, respectively; p < 0.031). The 35-day mortality rate was 4.1% for reteplase and 8.4% for alteplase (p = not significant). Reteplase and alteplase did not differ significantly with regard to the occurrence of severe bleeding (12.4% vs 9.7%, respectively) or hemorrhagic stroke (1.2% vs 1.9%, respectively). The results of these trials show that reteplase, given as a 10 + 10 U double bolus, achieves significantly higher rates of early reperfusion of the infarct-related coronary artery and is associated with significantly fewer acute coronary interventions when compared with front-loaded alteplase. The benefits of reteplase are achieved without any apparent increased risk of complications.

The initial work on thrombolytic therapy for acute myocardial infarction (AMI) focused on intracoronary administration of streptokinase. Continuing research has given rise to the development of both second- and third-generation agents and consequent refinements in thrombolytic regimens. Intravenous recombinant tissue plasminogen activator (t-PA, or alteplase) proved superior to both intracoronary and intravenous streptokinase with regard to reperfusion efficacy and impact on survival. An accelerated dosage regimen was later devised to allow the administration of t-PA over a shorter period of time. Unfortunately, t-PA failed to lessen the risk of bleeding complications that had plagued the use of streptokinase. The wild-type t-PA molecule has since been modified in an attempt to achieve improved lytic characteristics with less bleeding risk. Among these third-generation agents is reteplase (r-PA); compared with alteplase, reteplase has a prolonged half-life and seems to offer more rapid thrombolysis. Promising results have been obtained in large, randomized trials of reteplase. Another new agent is the TNK mutant of t-PA, which also has a prolonged half-life and seems to produce more rapid and complete thrombolysis, as well as less risk of intracranial bleeding than with alteplase in animal models. Although large, randomized trials have not yet been conducted, encouraging results have emerged from preliminary dose-ranging trials with TNK. A third new agent, n-PA, has an even longer half-life and has shown improved lytic activity in animal models. A dose-ranging trial of n-PA is currently under way. Despite the fact that each of the third-generation drugs has shown considerable potential with regard to improving the efficacy of thrombolytic therapy, the risk of intracranial bleeding remains problematic and will need to be assessed in large, randomized trials.

Prostaglandin E1 (PGE1) reduces experimental infarct size when administered by prolonged low-dose left atrial infusion during coronary occlusion. Liposomal delivery of PGE1 may enhance biologic activity and limit adverse hemodynamic effects. The purpose of this study was to test the hypothesis that intravenous bolus administration of liposomal PGE1 (TLC C-53, The Liposome Company, Princeton, N.J.) during coronary occlusion would result in myocardial salvage. We compared TLC C-53 (0.5 microgram/kg intravenous bolus at 10 and 100 min of occlusion of the left anterior descending coronary artery [LAD]), free PGE1 (0.1 microgram/kg/min infused 10 min after LAD occlusion until reperfusion), placebo liposomes, and control (n = 7 for each group) in an open-chest canine model of 2 hours of LAD occlusion and reperfusion. Infarct size as a percentage of risk area (mean +/- SD) in the control group (58.4% +/- 20.0%) was similar to that in animals given placebo liposomes (53.1% +/- 12.6%) but was significantly reduced in the groups given TLC C-53 (33.5% +/- 9.2%; p < 0.01) or free PGE1 (37.2% +/- 4.8%; p < 0.05) groups. Infarct salvage was significant (p < 0.05) for the TLC C-53-and PGE1-treated dogs compared with the control dogs, independent of collateral blood flow by analysis of covariance. Moreover, the ischemic-zone blood flow during reperfusion was significantly higher in the TLC C-53 group compared with the control group or the group receiving free PGE1. Neutrophil infiltration of ischemic myocardium was significantly inhibited by TLC C-53 as determined by myeloperoxidase assay. Unlike free PGE1, TLC C-53 did not cause significant tachycardia or hypotension during therapy. In conclusion, TLC C-53 administered intravenously during coronary occlusion significantly reduced infarct size, limited neutrophil infiltration, and improved myocardial blood flow during reperfusion without adverse hemodynamic consequences.

Background: The therapeutic benefit of thrombolytic therapy has been shown to correlate directly with completeness (TIMI grade 3 flow) and speed of reperfusion of the infarct-related coronary artery. The purpose of the RAPID II study was to determine whether a double-bolus regimen of reteplase, a recently developed deletion mutant of wild-type tissue plasminogen activator, could improve 90-minute coronary artery patency rates achieved with the most successful standard regimen, an "accelerated" front-loaded infusion of alteplase., Methods and Results: Three hundred twenty-four patients with acute myocardial infarction were randomized to receive (along with intravenous heparin and aspirin) either a 10 plus 10 megaunits double bolus of reteplase or front-loaded alteplase. The primary end point of "patency at 90 minutes, graded according to the TIMI classification" was centrally assessed in a blinded fashion. Infarctrelated coronary artery patency (TIMI grade 2 or 3) and complete patency (TIMI grade 3) at 90 minutes after the start of thrombolytic therapy were significantly higher in the reteplase-treated patients (TIMI grade 2 or 3: 83.4% versus 73.3% for front-loaded alteplase-treated patients, P = .03; TIMI grade 3: 59.9% versus 45.2%, P = .01). At 60 minutes, the incidence of both, patency and complete patency, was also significantly higher in reteplase-treated patients (reteplase versus alteplase, TIMI grade 2 or 3: 81.8% versus 66.1%, P = .01; TIMI grade 3: 51.2% versus 37.4%, P < .03). Reteplase-treated patients required fewer acute additional coronary interventions (13.6% versus 26.5%, P < .01), and 35-day mortality was 4.1% for reteplase and 8.4% for alteplase (P = NS). There were no significant differences between reteplase and alteplase in bleedings requiring a transfusion (12.4% versus 9.7%) or hemorrhagic stroke (1.2% versus 1.9%)., Conclusions: Reteplase, when given as a double bolus of 10 plus 10 megaunits to patients with acute myocardial infarction, achieves significantly higher rates of early reperfusion of the infarct-related coronary artery and requires significantly fewer acute coronary interventions than front-loaded alteplase without an apparent increased risk of complications.

Objectives: The purpose of this study was to identify qualitative or quantitative variables present on angioscopy, intravascular ultrasound imaging or quantitative coronary arteriography that were associated with adverse clinical outcome after coronary intervention in high risk patients., Background: Patients with acute coronary syndromes and complex lesion morphology on angiography are at increased risk for acute complications after coronary angioplasty. Newer devices that primarily remove atheroma have not improved outcome over that of balloon angioplasty. Intravascular imaging can accurately identify intraluminal and intramural histopathologic features not adequately visualized during coronary arteriography and may provide mechanistic insight into the pathogenesis of abrupt closure and restenosis., Methods: Sixty high risk patients with unstable coronary syndromes and complex lesions on angiography underwent angioscopy (n = 40) and intravascular ultrasound imaging (n = 46) during interventional procedures. In 26 patients, both angioscopy and intravascular ultrasound were performed in the same lesion. All patients underwent off-line quantitative coronary arteriography. Coronary interventions included balloon (n = 21) and excimer laser (n = 4) angioplasty, directional (n = 19) and rotational (n = 6) atherectomy and stent implantation (n = 11). Patients were followed up for 1 year for objective evidence for recurrent ischemia., Results: Patients whose clinical presentation included rest angina or acute myocardial infarction or who received thrombolytic therapy within 24 h of procedure were significantly more likely to experience recurrent ischemia after intervention. Plaque rupture or thrombus on preprocedure angioscopy or angioscopic thrombus after intervention were also significantly associated with adverse outcome. Qualitative or quantitative variables on angiography, intravascular ultrasound or off-line quantitative arteriography were not associated with recurrent ischemia on univariate analysis. Multivariate predictors of recurrent ischemia were plaque rupture on preprocedure angioscopy (p < 0.05, odds ratio [OR] 10.15) and angioscopic thrombus after intervention (p < 0.05, OR 7.26)., Conclusions: Angioscopic plaque rupture and thrombus were independently associated with adverse outcome in patients with complex lesions after interventional procedures. These features were not identified by either angiography or intravascular ultrasound.

The Bard Atherectomy Catheter is a new rotational atherectomy device that consists of a flexible, hollow, thin-walled cutting catheter that, while rotated at 1,500 revolutions per minute, is advanced across the lesion over a special spiral guidewire system. We report the initial clinical experience with this device in 20 peripheral lesions in ten patients. The majority of patients were treated for limb salvage. All lesions were successfully intervened on by atherectomy followed by adjunctive balloon angioplasty. A reduction to less than 50% stenosis was achieved in 13 of the 20 lesions (65%) after atherectomy but in all 20 lesions (100%) after adjunctive angioplasty for all lesions and stenting for dissections in two. Baseline minimal lesion lumen diameter was 0.8 +/- 0.7 mm with a reference vessel diameter of 4.2 +/- 1.7 mm (75 +/- 21% stenosis). The lumen improved to 2.0 +/- 0.8 mm (45 +/- 19% stenosis) (P < 0.001) following atherectomy and to 3.9 +/- 1.9 mm (13 +/- 16% stenosis) (P < 0.001) after adjunctive angioplasty. The average weight of removed atheroma was 45 +/- 58 mg. All ten patients had initial improvement in symptoms. At 6 months follow-up there was persistent improvement in eight patients and two subjects had undergone amputations. Our early clinical experience with this low profile, flexible atherectomy device, that enables extraction of a large amount of atheroma, suggests that it will become a valuable addition to current atherectomy technologies in small- and medium-sized vessels. The value of this device in coronary vessels is under investigation.

Background: The presence of angiographically identified intracoronary thrombus has been variably associated with complications after coronary angioplasty. Angiography has been shown to be less sensitive than angioscopy for detecting subtle details of intracoronary morphology, such as intracoronary thrombi. The clinical importance of thrombi detectable by angioscopy but not by angiography is not known., Methods and Results: Percutaneous coronary angioscopy was performed in 122 patients undergoing conventional coronary balloon angioplasty (PTCA) at six medical centers. Unstable angina was present in 95 patients (78%) and stable angina in 27 (22%). Therapy was not guided by angioscopic findings, and no patient received thrombolytic therapy as an adjunct to angioplasty. Coronary thrombi were identified in 74 target lesions (61%) by angioscopy versus only 24 (20%) by angiography. A major in-hospital complication (death, myocardial infarction, or emergency bypass surgery) occurred in 10 of 74 patients (14%) with angioscopic intracoronary thrombus, compared with only 1 of 48 patients (2%) without thrombi (P = .03). In-hospital recurrent ischemia (recurrent angina, repeat PTCA, or abrupt occlusion) occurred in 19 of 74 patients (26%) with angioscopic intracoronary thrombi versus only 5 of 48 (10%) without thrombi (P = .03). Relative risk analysis demonstrated that angioscopic thrombus was strongly associated with adverse outcomes (either a major complication or a recurrent ischemic event) after PTCA (relative risk, 3.11; 95% CI, 1.28 to 7.60; P = .01) and that angiographic thrombi were not associated with these complications (relative risk, 0.85; 95% CI, 0.36 to 2.00; P = .91)., Conclusions: The presence of intracoronary thrombus associated with coronary stenoses is significantly underestimated by angiography. Angioscopic intracoronary thrombi, the majority of which were not detected by angiography, are associated with an increased incidence of adverse outcomes after coronary angioplasty.

Vasospasm following balloon angioplasty of gastroepiploic artery bypass grafts can be prevented or reversed with vasodilators. In our patient, stent deployment for ostial stenosis of a free gastroepiploic artery graft was accompanied by severe, diffuse spasm and a change in graft configuration that required both intensive medical therapy and balloon angioplasty for resolution.

The vast majority of failures of transcatheter interventions in patients with peripheral vascular disease are due to inability to cross the lesion with a guidewire. Although the use of the Glidewire has clearly improved the success rate, failures with especially chronic total occlusions still occur. We describe a new technique using the very stiff backend of the Glidewire, which we have found very successful, when conventional techniques fall in crossing highly resistant lesions.

Background: Prostaglandin E1 (PGE1) inhibits leukocyte and platelet function and reduces infarct size during left atrial infusion. Intravenous liposomal PGE1 (TLC C-53) accelerates thrombolysis and prevents reocclusion in canine coronary thrombosis. We tested the hypothesis that intravenous TLC C-53 would attenuate reperfusion injury in a canine infarction-reperfusion model., Methods and Results: Twenty-one open-chest dogs were randomized to receive a 10-minute intravenous infusion of either liposome diluent (placebo), free PGE1 (2 micrograms/kg), or TLC C-53 (2 micrograms/kg PGE1) after 2 hours of left anterior descending (LAD) occlusion just before reperfusion. Hemodynamic assessment, regional myocardial blood flow determination with radioactive microspheres, myocardial leukocyte infiltration by myeloperoxidase assay, and estimation of infarct size using triphenyl tetrazolium chloride staining were performed. Regional fractional shortening was measured with sonomicrometer crystals implanted in the midmyocardium. Infarct size as a percentage of the risk region was significantly reduced (P < .05) with TLC C-53 (37.9 +/- 17.4%) compared with PGE1 (56.7 +/- 13.9%) or placebo (58.0 +/- 9.9%) infusion. Infarct salvage with TLC C-53 was independent of collateral blood flow by ANCOVA. There was a dramatic reduction in myeloperoxidase activity in the infarct, risk, and border regions of dogs treated with TLC C-53 compared with placebo. Enzyme activity was also significantly reduced (P < .05) in the infarct zone with TLC C-53 (0.11 +/- 0.1 U/100 mg) treatment compared with PGE1 (0.38 +/- 0.3 U/100 mg). No significant differences in regional myocardial blood flow or myocardial function among treatment groups were identified, although there was a trend toward improved function in the TLC C-53 dogs., Conclusions: Bolus intravenous administration of TLC C-53 immediately before reperfusion results in reduced leukocyte infiltration and substantial infarct salvage. TLC C-53 mah be useful in limiting reperfusion injury during treatment of acute myocardial infarction.

Background: Early restoration and maintenance of normal (TIMI 3) blood flow during acute myocardial infarction is critical for optimal preservation of left ventricular function and survival. Recombinant plasminogen activator (r-PA, reteplase) is a nonglycosylated deletion mutant of wild-type tissue-type plasminogen activator (TPA) that has been shown to achieve more rapid and complete thrombolysis compared with other plasminogen activators in animal models., Methods and Results: The RAPID Trial was designed to test the hypothesis that bolus administration of one or more dosage regimens of r-PA was superior to standard-dose alteplase (TPA) in achieving infarct-related artery patency 90 minutes after initiation of treatment. Six hundred six patients with acute myocardial infarction were randomized to one of four treatment arms: (1) TPA 100 mg i.v. over 3 hours, (2) r-PA as a 15-MU single bolus, (3) r-PA as a 10-MU bolus followed by 5 MU 30 minutes later, or (4) r-PA as a 10-MU bolus followed by 10 MU 30 minutes later. Coronary arteriography was performed at 30, 60, and 90 minutes after initiation of treatment and at hospital discharge. The 10 + 10-MU r-PA group achieved better 90-minute and 5- to 14-day TIMI 3 flow (63% [CI, 55% to 71%] versus 49% [41% to 57%], P = .019, and 88% [82% to 94%] versus 71% [63% to 79%], P < .001, respectively) than the TPA group. The TIMI 3 flow in the 10 + 10-MU r-PA group at 60 minutes was equivalent to that in the TPA group at 90 minutes (51 versus 49%). Global ejection fraction and regional wall motion in the 10 + 10-MU r-PA group were superior to those of the TPA group at hospital discharge (53 +/- 1.3% versus 49 +/- 1.3%, P = .034; -2.19 +/- 0.12 versus -2.61 +/- 0.13 SD per chord, P = .02, respectively). The 15-MU and 10 + 5-MU r-PA patency and left ventricular function results were similar to those of the TPA and inferior to those of the 10 + 10-MU r-PA group. Bleeding complications were similar between the groups., Conclusions: r-PA given as a double bolus of 10 + 10 MU achieves more rapid, complete, and sustained thrombolysis of the infarct-related artery than standard-dose TPA, without an apparent increased risk of complications. This was associated with improved global and regional left ventricular function at hospital discharge.

Myocardial necrosis progresses with the duration of coronary occlusion in the early stages of acute myocardial infarction. Prompt recanalization of the infarct-related artery resulting in effective and sustained reperfusion of jeopardized myocardium is the goal of modern therapy. Clinical thrombolysis trials have demonstrated a significant survival advantage for treated patients, but only a modest recovery of global or regional systolic left ventricular function. Accelerated regimens of administering currently available thrombolytic agents are associated with early coronary patency rates approaching 85%, although effective coronary perfusion is restored in only slightly better than one half of patients treated. Primary angioplasty without antecedent thrombolytic therapy has resulted in high patency rates with superior coronary flow when performed in some experienced centers. Treatment of cardiogenic shock requires immediate mechanical or surgical intervention to reestablish coronary perfusion often following placement of a circulatory assistance device. Future trends toward very early initiation of thrombolytic therapy, improvements in adjunctive therapy and advances in the noninvasive detection of recanalization should permit selective use of aggressive interventional therapy for failed thrombolysis in a minority of patients with acute myocardial infarction.