Fate of patients with acute myocardial infarction with patency of the infarct-related vessel achieved with successful thrombolysis versus rescue angioplasty.

Patients with failure of infarct-related artery recanalization after thrombolytic therapy have a poor clinical outcome. These patients have been considered for rescue angioplasty 90 min after thrombolytic therapy at the time of emergency catheterization in the course of five Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) trials. The outcome of 776 patients with patent infarct-related vessels after emergency catheterization was analyzed--607 with thrombolysis-mediated patency of the infarct-related vessel and 169 with patency achieved by angioplasty. Baseline characteristics of the thrombolysis and angioplasty patency groups were similar except for a higher acute left ventricular ejection fraction (51.3% versus 48.2%) in the thrombolysis group (p = 0.003). Seven to 10 day left ventricular ejection fraction was higher (52.3% versus 48.1%), infarct zone functional recovery was greater (0.44 versus 0.21 standard deviation/chord, or 18% versus 7%, p = 0.001) and reocclusion was less (11% versus 21%) in the thrombolysis compared with the angioplasty group. Despite these differences, angioplasty patency was associated with the same low in-hospital mortality rate (5.9% versus 4.6%) and long-term mortality rate (3% versus 2%) as thrombolysis patency. Reocclusion adversely affected the mortality rate and ventricular functional recovery. Technical failure of rescue angioplasty was associated with a much higher mortality rate than was technical success (39.1% versus 5.9%). Thrombolysis patency was preferable to angioplasty patency after thrombolytic therapy in acute myocardial infarction, but both were associated with the same low in-hospital and long-term mortality rates, suggesting that rescue angioplasty is beneficial in some patients with failure of infarct-related artery recanalization after thrombolytic therapy.     

Reocclusion: The flip side of coronary thrombolysis

Since the introduction of thrombolytic therapy for acute myocardial infarction, the incidence of coronary artery reocclusion has been intensively studied. Also, the prediction and diagnosis of reocclusion by angiographic and clinical variables, as well its invasive and pharmacologic prevention, have gained much attention.By angiographic definition, reocclusion requires three angiographic observations: one with an occluded artery, one with a reperfused artery and a third for the assessment of subsequent occlusion (true reocclusion). Since the introduction of early intravenous reperfusion therapy, most studies use only two angiograms: one with a patent and one with a nonpatent infarct-related artery. A search for all published reocclusion studies revealed 61 studies (6,061 patients) with at least two angiograms. The median time interval between the first angiogram after thrombosis and the second was 16 days (range 0.1 to 365). Reocclusion was observed in 666 (11%) of 6,061 cases. Interestingly, the 28 true reocclusion studies showed an incidence of reocclusion of 16 ± 10% (mean ± SD), and the 33 studies with only two angiograms 10 ± 8% (p = 0.04), suggesting that proven initial occlusion of the infarct-related artery is a risk factor for reocclusion after successful thrombolysis. The other predictors for reocclusion are probably severity of residual stenosis of the infarct-related artery after thrombolysis and perhaps the flow state after lysis. Reocclusion is most frequently seen in the early weeks after thrombolysis. The clinical course in patients with reocclusion is more complicated than in those without complication. Left ventricular contractile recovery after thrombolysis is hampered by reocclusion.Routine invasive strategies have not been proven effective against reocclusion. In the prevention of reocclusion, both antiplatelet and antithrombin strategies have been tested, including hirudin and hirulog, but the safety of these agents in thrombolysis is still questionable.Thus, reocclusion after thrombolysis is an early phenomenon and is more frequent after proven initial occlusion of the infarct-related artery. Reocclusion can be predicted by angiography after thrombolysis. Because reocclusion is detrimental, strategies to prevent it should be developed and carried out after thrombolytic therapy for acute myocardial infarction as soon as they are deemed safe.     

Improvement in three-month angiographic outcome suggested after primary angioplasty for acute myocardial infarction (Zwolle trial) compared with successful thrombolysis (APRICOT trial). Antithrombotics in the Prevention of Reocclusion In COronary Thrombolysis.

It has been shown that primary percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction results in higher patency rates than thrombolytic therapy. However, no data are available on differences in long-term angiographic outcome after successful primary PTCA compared with successful thrombolysis. Therefore, we compared angiographic data of the Antithrombotics in the Prevention of Reocclusion In COronary Thrombolysis (APRICOT) trial and the Zwolle primary PTCA trial. In the APRICOT trial 248 patients underwent coronary angiography at a mean of 24 hours after thrombolysis and had a patent infarct-related vessel (Thrombolysis In Myocardial Infarction-3 trial flow) when entering the study. Reocclusion rates were assessed at a second angiography after 3 months. In the Zwolle trial 136 patients had a successful primary PTCA. At 3 months 131 patients underwent a second angiography. Quantitative coronary angiography showed a significant lower mean diameter stenosis of the infarct-related vessel after primary PTCA (27 +/- 12% vs 57 +/-12%; p = 0.00001). At 3 months this difference was sustained (35 +/- 22% vs 63 +/- 26%; p = 0.00001). After thrombolysis the reocclusion rate at 3 months was 29% compared with 5% after primary PTCA (p = 0.0001). Results show that compared with successful thrombolytic therapy, primary PTCA for acute myocardial infarction results in an improved infarct-related vessel status not only short term but also long term, with a low reocclusion rate.     

Frequent reocclusion of patent infarct-related arteries between 4 weeks and 1 year: Effects of antiplatelet therapy

Objectives. This study assessed the effect of the combination of aspirin and dipyridamole on patency of the infarct-related artery between 4 weeks and 1 year after myocardial infarction.Background. Patency of the infarct-related artery is an important determinant of prognosis after myocardial infarction. The incidence of late reocclusion and the effects of antiplatelet therapy are unknown.Methods. To investigate the importance of antiplatelet therapy for the prevention of late reocclusion, 215 patients who had a patent infarct-related artery 4 weeks after myocardial infarction were randomized in a double-blind manner to receive either a combination of 25 mg of aspirin and 200 mg of dipyridamole twice daily or placebo. One hundred fifty-four patients underwent further coronary arteriography 1 year later.Results. At 1 year, 38 (25%) of 154 patients had reocclusion of the infarct-related artery; 18 (23%) of 79 patients receiving aspirin and dipyridamole had late reocclusion versus 20 (27%) of 75 who received placebo (p = NS). The rate of reocclusion was related to the severity of the residual coronary artery stenosis at 4 weeks (<50% stenosis 9.2%; 50% to 69% stenosis 11.6%; 70% to 89% stenosis 30.4%; ≥ 90% stenosis 70%, p < 0.01). The majority of reocclusions were silent, and only 17 (45%) of 38 were clinically associated with further infarction. There were no differences for a hierarchic end point of cardiac death, myocardial infarction or revascularization (14.8% aspirin and dipyridamole vs. 17.8% placebo).Conclusions. Late reocclusion of the patent infarct-related artery is a frequent event, occurring in 25% of patients. Antiplatelet therapy with the combination of aspirin and dipyridamole does not alter the overall rate of late reocclusion. Other strategies are required to reduce late reocclusion.     

Percutaneous transluminal coronary angioplasty in evolving acute myocardial infarction

In 29 patients with evolving acute myocardial infarction, acute reperfusion of the infarct-related coronary artery was attempted using percutaneous transluminal coronary angioplasty (PTCA). Before PTCA, angiography showed 23 totally occluded and 6 severely stenotic infarct-related coronary arteries. PTCA was initially successful in 25 of 29 patients (86%). Reocclusion occurred in 4 patients within 12 hours after successful PTCA and was associated with new electrocardiographic changes or recurrence of symptoms. In 17 patients the infarct-related coronary artery remained patent at early follow-up; late stenosis occurred in 4 patients. Recurrence of stenosis was accompanied by development of angina. No clinical or angiographic features distinguished those with ultimate vessel patency, occlusion or recurrence of stenosis. On follow-up, ventricular function appeared better preserved or improved in those with a patent infarct-related coronary artery than in those with an occluded infarct-related coronary artery. Further studies are warranted to compare PTCA and streptokinase as primary reperfusion modalities in evolving acute myocardial infarction.     

Combination thrombolytic therapy: a comparison of simultaneous and sequential regimens of tissue plasminogen activator and urokinase

Coronary angioplasty following unsuccessful tissue plasminogen activator (t-PA) therapy for acute myocardial infarction has been associated with a high incidence of subsequent reocclusion of the infarct-related artery, and a relatively high in-hospital mortality. In contrast, the combination of t-PA and urokinase, when given intravenously prior to coronary angiography, appears to be associated with a low incidence of post-rescue angioplasty reocclusion. In order to determine whether intraprocedural urokinase, given at the time of rescue coronary angioplasty for failed t-PA therapy, improves long-term patency of the infarct vessel to the same extent as preangiographic, combination t-PA/urokinase therapy, three thrombolytic treatment strategies were retrospectively compared. The first group included 86 patients undergoing rescue angioplasty after t-PA monotherapy (t-PA alone). The clinical and angiographic outcomes of these patients were compared with those of 24 patients who received intravenous or intracoronary urokinase during rescue angioplasty following unsuccessful t-PA therapy (sequential t-PA/urokinase therapy), and with those of 34 patients undergoing rescue coronary angioplasty following unsuccessful therapy with the combination of intravenous t-PA and urokinase (simultaneous therapy). There was no difference in postangioplasty patency rate of the infarct-related artery between the three groups. However, the sequential t-PA/urokinase regimen was associated with a subsequent reocclusion rate that was lower than the rate that occurred in the t-PA monotherapy group but higher than the rate in the simultaneous t-PA/urokinase group (13 versus 29 versus 2%, respectively; p = 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)     

Combination of inhibition of thrombin and blockade of thromboxane A2 synthetase and receptors enhances thrombolysis and delays reocclusion in canine coronary arteries.

BACKGROUND. The efficacy of thrombolytic therapy in treating patients with acute myocardial infarction is limited by failure to achieve reperfusion in some patients, by the prolonged time required to achieve reperfusion, and by reocclusion of some coronary arteries. We designed this study to examine the effect of combined inhibition of thrombin and thromboxane synthesis and blockade of thromboxane A2 receptors in addition to tissue-type plasminogen activator (t-PA) on thrombolysis and reocclusion in an experimental canine model with coronary thrombosis. METHODS AND RESULTS. Blood flow velocity in the left anterior descending coronary artery (LAD) of 32 anesthetized mongrel dogs was monitored by a pulsed Doppler flow probe. Coronary thrombosis was induced by applying electrical stimulation to the LAD at the site where an external constrictor was used to narrow the artery. Three hours after the formation of occlusive thrombus, animals were randomly assigned to receive one of the following: 1) t-PA (80 micrograms/kg + 8 micrograms.kg-1.min-1 i.v.) and saline; 2) t-PA and hirulog, a hirudin-based synthetic peptide and specific thrombin inhibitor (2 mg/kg + 2 mg.kg-1.hr-1 i.v.); 3) t-PA and ridogrel, a combined thromboxane A2 synthetase inhibitor and receptor antagonist (5 mg/kg + 2.5 mg.kg-1.hr-1 i.v.); or 4) t-PA, hirulog, and ridogrel. Reperfusion developed in 14% (one of seven) of dogs treated with t-PA alone at an average of 86 +/- 4 minutes after treatment, in 78% (seven of nine) of dogs treated with t-PA plus hirulog at 53 +/- 11 minutes, in 13% (one of eight) of dogs treated with t-PA plus ridogrel at 85 +/- 5 minutes, and in 88% (seven of eight) of dogs treated with t-PA, hirulog, and ridogrel at 37 +/- 10 minutes (comparison of the frequency of and the time to reperfusion, both p < 0.01). Among the dogs with reestablished coronary blood flow, reocclusion developed in the one treated with t-PA alone at 36 minutes after reperfusion, in seven of the seven treated with t-PA plus hirulog at 66 +/- 15 minutes, and in two of the seven treated with t-PA, hirulog, and ridogrel at 151 +/- 21 minutes (comparison of the frequency of and time to reocclusion, both p < 0.05). Reocclusion was not detected in the one dog treated with t-PA and ridogrel or in the other five dogs treated with t-PA, hirulog, and ridogrel within 180 minutes after reperfusion. Hirulog prolonged and maintained activated clotting times at a level twice that of baseline values. Hirulog inhibited ex vivo platelet aggregation induced by thrombin, and ridogrel inhibited platelet aggregation induced by U46619, a thromboxane mimetic. CONCLUSIONS. Inhibition of thrombin in addition to treatment with t-PA enhances thrombolysis. A combination of inhibition of thrombin and thromboxane synthetase and blockade of thromboxane A2 receptor enhances thrombolysis and delays or may prevent reocclusion of the recanalized coronary arteries.     

Reperfusion, patency and reocclusion with anistreplase (APSAC) in acute myocardial infarction

Because the reestablishment of coronary blood flow is believed to be central to the benefit of thrombolytic therapy, measurements of reperfusion (i.e., angiography before and after therapy), patency (i.e., angiography after therapy) and reocclusion rates are important to the evaluation of new thrombolytic therapies. For anisoylated plasminogen streptokinase activator complex (APSAC, anistreplase), comparisons have been made with control or placebo therapies to assess absolute efficacy, and with streptokinase to assess relative efficacy. In pooled experience from reperfusion studies, APSAC (30 U over 2 to 5 minutes) led to angiographic reperfusion in 55% of patients (98 of 177) who had symptoms of acute myocardial infarction (MI) for less than 6 hours. Among 107 patients treated with APSAC in angiographic patency studies, 69% (74) showed an open infarct-related artery 1 to 4 hours after therapy. (Patency rates are generally 10 to 20% greater than reperfusion rates, because some patients with acute MI may have a patent [subtotally occluded or spontaneously reperfused] infarct-related artery when entered into patency studies.) Using early peaking (less than or equal to 15 hours) of the creatine kinase curve as an indicator, a patency rate of 63% was observed among 387 patients treated with APSAC. The initial success rate with thrombolytic therapies is diminished by the rates of reocclusion and reinfarction, which must be accounted for in determining the net success of therapy. In 6 studies, a total of 87 patients with initially patent arteries after APSAC returned for reevaluation in 1 to 3 days.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of new antiplatelet agents as adjunctive therapies in thrombolysis

Coronary thrombolysis is the treatment of choice for patients with acute Q-wave myocardial infarcts who have no contraindications to such therapy. However, the time required for thrombolysis and the possibility of reocclusion of the infarct-related artery remain problematic. Herein are described experimental animal studies and clinical evaluations in which attempts have been made to develop adjunctive therapies that, when coupled with available thrombolytic interventions, might shorten the time to thrombolysis and delay or prevent reocclusion. From the studies conducted to date, it is clear that a combined thromboxane synthesis inhibitor and receptor antagonist with a serotonin receptor antagonist and heparin shorten the time to thrombolysis and delay or prevent coronary artery reocclusion in experimental canine models with copper coil-induced coronary artery thrombi. A monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor coupled with tissue plasminogen activator (t-PA) and heparin also shortens the time to thrombolysis and delays or prevents reocclusion in experimental canine models. Thrombin inhibitors, including heparin and synthetic inhibitors, given with t-PA and aspirin, appear to shorten the time to thrombolysis and delay or prevent coronary artery reocclusion in experimental canine models. Aspirin coupled with intravenous streptokinase reduces mortality in patients with presumed acute myocardial infarction, and a combination of heparin and t-PA results in infarct-artery patency more frequently than t-PA without heparin. Data from these studies are encouraging with regard to the possibility of developing effective and relatively safe thrombolytic regimens that shorten the time to thrombolysis and delay or prevent coronary artery reocclusion.     

Infarct artery reocclusion after primary angioplasty, stent placement, and thrombolytic therapy for acute myocardial infarction

BACKGROUND: The benefits of thrombolytic therapy for acute myocardial infarction (AMI) are limited by reocclusion of the infarct-related artery, which occurs in 25% to 30% of patients after successful reperfusion. The frequency of reocclusion after balloon angioplasty and stenting in this setting is less well documented. The aim of this study was to analyze the frequency and timing of reocclusion after percutaneous transluminal coronary angioplasty (PTCA) and stent placement during AMI from all available studies compared with previously published reocclusion rates after thrombolysis. METHODS AND RESULTS: The previously published thrombolysis data included 4231 patients in 19 studies with > or = 75 patients. Only PTCA studies with > or = 50 patients and stent studies with > or = 30 patients, in which routine angiographic follow-up was obtained in > or = 60% of patients, were included. Ten PTCA studies with a total of 1943 patients were analyzed, with follow-up angiography in 1391 (72%). Reocclusion rates ranged from 5% to 16.7%. The stent studies included 698 patients from 7 studies, with follow-up angiography in 92%. Reocclusion rates ranged from 0% to 6%. With the use of logistic regression analysis with allowance for overdispersion, there was a significantly lower rate of reocclusion after PTCA (odds ratio, 0.38; confidence interval, 0.24 to 0.57; P <.0001) and stent placement (odds ratio, 0.11; confidence interval, 0.05 to 0.22; P <.0001) compared with thrombolysis. Reocclusion after stent placement was lower than after PTCA (odds ratio, 0.28; confidence interval, 0.13 to 0.6; P <.0001). CONCLUSIONS: Reocclusion after PTCA and stent placement during AMI is less frequent than after thrombolysis. This may contribute to the superior outcome of patients treated with PTCA and stent placement in this setting.     

Effect of coronary reocclusion after initial reperfusion on ventricular function and infarct size

Reocclusion of a coronary artery after thrombolytic therapy occurs in approximately 12% to 33% of patients; however, there are few experimental data concerning reocclusion. Accordingly, to compare the effects of reocclusion versus sustained occlusion on the myocardium, a canine model (n = 12) of 2 h of left circumflex artery occlusion, 1 h of reperfusion and 1 h of reocclusion was studied. In a control group (n = 11), 3 h of circumflex artery occlusion was followed by 1 h of reperfusion. As a result, both groups had the same total duration of ischemia (3 h) and reperfusion (1 h). Hemodynamic measurements, radioactive microsphere injections and two-dimensional echocardiography were performed at baseline, occlusion and reperfusion for both groups and at the end of reocclusion for the experimental group. In vivo risk area was determined with Evans blue dye and infarct size with triphenyltetrazolium staining methods. Similar decreases in myocardial blood flow after coronary occlusion and similar reperfusion blood flows occurred in both groups. Despite intervening reperfusion in the reocclusion group, no significant difference was found in the infarct size/risk area ratio between the reocclusion and control groups (54.5 +/- 6.9% vs. 48.4 +/- 5.1%, respectively, p = NS). Two-dimensional echocardiography demonstrated a similar degree and extent (159 +/- 9 degrees vs. 153 +/- 12 degrees, p = NS) of left ventricular dysfunction with both the occlusion and reocclusion. In addition, there were no significant differences in global or regional left ventricular function between the two groups. However, reocclusion after reperfusion did produce a further deterioration in ischemic zone wall thickening (9.5 +/- 2.0% to 0.7 +/- 1.8%, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Intravenous recombinant tissue plasminogen activator (rt-PA) and urokinase in acute myocardial infarction: results of the German Activator Urokinase Study (GAUS)

The effects of recombinant tissue plasminogen activator (rt-PA) and urokinase on patency and early reocclusion of infarct-related coronary arteries were investigated in a single blind, randomized multicenter trial in 246 patients with acute myocardial infarction of less than 6 h duration. Both 70 mg of single chain rt-PA with an initial bolus of 10 mg and 3 million units of urokinase with an initial bolus of 1.5 million units were given intravenously over 90 min. The first angiographic study at the end of the infusion revealed a patent infarct-related artery (Thrombolysis in Myocardial Infarction trial [TIMI] grade 2 or 3) in 69.4% of 121 patients given rt-PA versus 65.8% of 117 patients given urokinase (p = NS). Among patients treated within 3 h from symptom onset a patent infarct-related artery was found in 63.9% of 72 patients given rt-PA versus 70% of 70 patients given urokinase (p = NS). There were five cardiac deaths in each group and one fatal intracranial hemorrhage in the rt-PA group. The in-hospital reinfarction rate was 8.9% versus 13.2% for patients treated with rt-PA and urokinase, respectively. There was no difference in left ventricular function at baseline and follow-up catheterization studies. Both drugs were well tolerated and there was no significant difference in cardiovascular or bleeding complications between the two groups. It is concluded that rt-PA and urokinase in the dosages used provide similar efficacy and safety in the treatment of acute myocardial infarction. Reocclusion during the first 24 h may be less frequent after urokinase treatment.     

Efficacy of Streptokinase,but Not Tissue-Type Plasminogen Activator,in Achieving 90-Minute Patency After Thrombolysis for Acute Myocardial Infarction Decreases With Time to Treatment

Objectives. We sought to examine the relation between time to treatment and 90-min patency rates in patients receiving intravenous streptokinase (SK) or accelerated tissue-type plasminogen activator (t-PA).Background. Early patency of the infarct-related artery is a major determinant of survival after thrombolysis for acute myocardial infarction. Some data suggest that time to treatment may influence the efficacy of nonfibrin-specific thrombolytic agents in restoring early patency of the infarct-related vessel.Methods. We performed a retrospective analysis of a cohort of 481 patients receiving thrombolytic therapy for acute myocardial infarction <6 h after pain onset, all of whom underwent 90-min coronary angiography. Patency of the infarct-related artery was graded by two observers who had no knowledge of the treatment received or the time between pain and therapy.Results. There was no difference in baseline clinical or angiographic characteristics according to the timing or nature of treatment. Thrombolysis in Myocardial Infarction (TIMI) flow grade 2 or 3 patency rate after SK correlated negatively with the time between onset of pain and thrombolysis (r = 0.8, p = 0.05), whereas the 90-min patency rate after t-PA appeared stable as a function of time to treatment. When patients were categorized as having received treatment <3 or ≥3 h after pain onset, the patency rate was similar with t-PA, but significantly higher when SK was administered early rather than late, regardless of whether TIMI flow grades 2 and 3 were pooled (86.9% vs. 59.4%, p = 0.0001) or TIMI flow grade 3 alone was considered to indicate patency (81.7% vs. 53.6%, p = 0.0001). Multivariate logistic regression analysis showed a negative effect of time to treatment on the patency probability for SK (p = 0.0001) but not for t-PA.Conclusions. The efficacy of streptokinase but not t-PA in restoring early coronary patency after intravenous thrombolysis is markedly lower when patients are treated later after onset of pain.     

Double bolus administration of the novel recombinant plasminogen activator BM 06.022 improves coronary blood flow after reperfusion in a canine model of coronary thrombosis.

Reocclusion of coronary arteries is a major problem after successful thrombolysis in patients with acute myocardial infarction. We evaluated in a canine model of coronary thrombosis which is known to elicit reocclusion, whether an increased single i.v. bolus dose or two boli of the novel t-PA variant BM 06.022 improved coronary blood flow after reperfusion compared to i.v. injection of a standard single dose of BM 06.022. Double bolus administration, but not an increased single bolus dose of BM 06.022 significantly increased the maximum achieved coronary blood flow, prolonged the cumulative patency time, maintained blood flow at the end of the experiments, and reduced residual thrombus wet weight. Thus, double bolus administration improves coronary blood flow after reperfusion in the dog.     

Percutaneous transluminal coronary angioplasty after intracoronary streptokinase in evolving acute myocardial infarction

To achieve optimal myocardial revascularization and prevent rethrombosis of the infarct-related coronary artery, percutaneous transluminal coronary angioplasty (PTCA) was attempted in 18 patients with evolving acute myocardial infarction (9 anterior and 9 inferior) after administration of intracoronary streptokinase. PTCA was attempted 338 +/- 151 minutes after the onset of symptoms. After thrombolytic therapy, 11 patients had a severe residual stenosis and 7 a persistent total occlusion of the infarct-related coronary artery. PTCA was successful in 13 of 18 patients: in 9 of 11 with coronary stenoses and in 4 of 7 with total coronary occlusions. PTCA reduced the severity of the coronary lesion from 91 +/- 2% to 27 +/- 7% (p less than 0.001), and the transstenotic pressure gradient from 38 +/- 5 to 6 +/- 2 mm Hg (p less than 0.01). One patient in cardiogenic shock died during urgent coronary surgery after unsuccessful PTCA. After PTCA, all patients received heparin and antiplatelet agents. One patient had reinfarction with reocclusion of the infarct-related artery 5 days after PTCA. The other 12 patients had an uneventful hospital course, and cardiac catheterization before hospital discharge (8 to 17 days) revealed reocclusion of the infarct-related coronary artery in 3 and persistent patency in 9. Persistent patency of the infarct-related artery was associated with preservation of left ventricular end-diastolic volume (initial 86 +/- 6 ml/m2, follow-up 91 +/- 6 ml/m2), and improvement in left ventricular ejection fraction in some patients.     

The late open artery hypothesis--a decade later

BACKGROUND: Early reperfusion after myocardial infarction has been proved to preserve left ventricular function and reduce mortality. However, a significant number of patients have persistent occlusion of the infarct-related artery late (days to weeks) after myocardial infarction because of ineligibility for thrombolytic therapy, failure of reperfusion, or reocclusion. METHODS: In this report we review the data on the potential mechanisms and benefits of late reperfusion and present prospective data on the incidence of and current practice patterns for the management of persistently occluded infarct-related arteries late after myocardial infarction. RESULTS: Although several studies have associated late patency of the infarct-related artery with improved long-term clinical outcome, they were nonrandomized and reflect selection bias. Furthermore, data on late patency from the largest study, Global Utilization of Steptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO-I), failed to confirm independent benefits of an open infarct-related artery 1 year after myocardial infarction. The randomized data on the effects of percutaneous transluminal coronary angioplasty for occluded infarct-related arteries late after myocardial infarction are limited and inconclusive. CONCLUSIONS: The hypothesis that late reperfusion by percutaneous coronary intervention days to weeks after myocardial infarction results in improved long-term clinical outcomes in asymptomatic patients with occluded infarct-related artery is currently being tested in the randomized, multicenter Occluded Artery Trial.     

ST segment analysis for assessment of coronary artery patency: comparison of surface ECG and Holter recordings.

In a prospective trial in 124 patients with acute myocardial infarction, Holter and surface ECG recordings were obtained simultaneously and compared for their ability to assess thrombolysis-induced ST segment changes. Accuracy in predicting patency of the infarct-related artery was evaluated in both methods. Success or failure of thrombolysis was determined angiographically 90 min after the start of therapy. For both methods, sensitivity, specificity, and positive predictive value for correct prediction of the perfusion status ranged between 64% and 92%. However, the negative predictive value was considerably lower (40-53%). There were no significant differences in any parameter evaluated for either method. Thus, two surface ECG recordings before and 2 h after the start of therapy yield the same predictive value as continuous Holter monitoring with respect to thrombolysis-induced coronary artery reperfusion. However, for triage of patients to early coronary interventions, more sophisticated methods are needed for non-invasive prediction of coronary artery patency due to the low negative predictive value of ST segment analysis.     

Prevention of coronary artery reocclusion and reduction in late coronary artery stenosis after thrombolytic therapy in patients with acute myocardial infarction. A randomized study of maintenance infusion of recombinant human tissue-type plasminogen activator

Sixty-eight patients with acute "transmural" myocardial infarction presenting within 6 hours (range, 1.3-5.8 hours) of onset of chest pain were given intravenous recombinant tissue-type plasminogen activator (rt-PA) at a dosage of 1 mg/kg during 90 minutes. Coronary angiography at 90 minutes revealed a patent infarct-related coronary artery in 52 patients (76%). These patients were randomized either to treatment by continuous infusion of heparin alone (27 patients) or to treatment by heparin and a maintenance infusion of rt-PA at a dosage of 0.8 mg/kg during 4 hours (25 patients). Coronary angiography was repeated 60 minutes after the start of the maintenance infusion and again after 8-14 days. Acute symptomatic reocclusion of the infarct-related artery occurred during the 1-hour observation period in five (19%) patients treated with heparin alone but in none of the patients treated with rt-PA (p = 0.05). The measured residual stenosis of the patent infarct-related coronary artery was similar in the heparin-treated and the rt-PA-treated groups at 90 minutes infusion: 66 +/- 14% versus 68 +/- 13% diameter stenosis, respectively (mean +/- SD) and 1.1 +/- 1.1 mm2 versus 0.82 +/- 0.7 mm2 area (p = 0.35). At 8-14 days after infusion, residual stenosis was unchanged in the heparin-treated group, but it improved to 55 +/- 17% (p = 0.001) and 1.6 +/- 1.2 mm2 (p = 0.003) in the rt-PA-treated group. At 90 minutes of infusion, residual intraluminal thrombus was observed in 29 of the 52 patients (56%) with a comparably measured distribution in the two groups (p = 0.43). At 150 minutes, however, the extent of intraluminal thrombus was significantly reduced in the rt-PA-treated group as compared with the heparin-treated group (p = 0.03). In-hospital ischemic events (symptomatic reocclusion, unstable angina, or cardiovascular death) occurred in 12 patients of the heparin-treated group but only in three patients of the rt-PA-treated group (p = 0.03). Fibrinogen levels decreased to 65 +/- 21% of baseline at 90 minutes of rt-PA infusion. During the rt-PA maintenance infusion, fibrinogen fell slightly from 63 +/- 26 to 57 +/- 28% (p = 0.18). This study shows that after successful reperfusion with 1 mg/kg rt-PA during 90 minutes, a maintenance infusion of 0.8 mg/kg rt-PA during 4 hours prevents acute symptomatic coronary artery reocclusion, and it reduces the frequency of ischemic events and the severity of residual coronary artery stenosis at hospital discharge.     

Combined tissue-type plasminogen activator and prostacyclin therapy for acute myocardial infarction. Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 4 Study Group

Current limitations of recombinant tissue-type plasminogen activator (rt-PA) therapy for acute myocardial infarction include failure to achieve recanalization in 25% of patients, reocclusion and reperfusion injury. Iloprost, a stable analogue of prostacyclin (PGI2), has been demonstrated to facilitate thrombolysis and reduce myocardial stunning in experimental models. To evaluate combined therapy, rt-PA (100 mg 3 h) and Iloprost (2 ng/kg per min for 48 h) were administered to 25 patients and then rt-PA alone (same dose) was given to an additional 25 patients with evolving myocardial infarction. At 90 min after drug administration, infarct-related vessel patency was observed in 11 (44%) of 25 who received rt-PA plus Iloprost compared with 15 (60%) of 25 who received rt-PA alone (p = 0.26). At 1 week, reocclusion had occurred in 3 (14%) of 21 patients who received combined therapy compared with 6 (26%) of 23 patients treated with rt-PA alone (p = 0.46). Ejection fraction increased significantly from baseline to 7 days for rt-PA alone whereas it decreased with combined therapy (rt-PA alone whereas it decreased with combined therapy (rt-PA alone: 47.3 +/- 11.5% at baseline to 50.4 +/- 9.8% at 7 days; rt-PA plus Iloprost: 51.3 +/- 10.1% at baseline to 49.0 +/- 9.4% at 7 days; difference between groups p = 0.05). At 4 h after therapy, fibrinogen decreased 33% for rt-PA plus Iloprost compared with a 52% for rt-PA alone (p = 0.001). Fibrinogen degradation products increased 60% more for rt-PA alone than for rt-PA plus Ilprost. Thus, the combination of rt-PA plus Iloprost at the doses employed did not improve immediate or follow-up coronary artery patency or left ventricular functional recovery compared with that achieved with rt-PA alone.     

Evaluation of a prolonged infusion of recombinant tissue-type plasminogen activator (Duteplase) in preventing reocclusion following successful thrombolysis in acute myocardial infarction.

The hypothesis that an infusion of recombinant tissue-type plasminogen activator (rt-PA) maintained for up to 24 hours could prevent reocclusion after early coronary patency had been established was evaluated in patients with acute myocardial infarction. The rt-PA studied was an investigational double chain rt-PA (Duteplase, Burroughs Wellcome Co.), administered according to body weight. Coronary patency was documented in 139 of 213 patients who had 90-minute angiograms recorded after an initial lytic dose of rt-PA. In these responders a further 90-minute infusion at one third the initial lytic dose was given before assignment to 1 of 4 maintenance dose rates (0.012, 0.024, 0.036, 0.048 MIU/kg/hour) which were continued for the subsequent 9 to 21 hours. The principal end point was the status of the infarct-related coronary artery 12 to 24 hours after the start of therapy, and before termination of rt-PA, in patients with initially patent vessels at 90 minutes. Of the 103 responders with repeat angiograms after a 9 to 21 hour maintenance infusion of rt-PA, a total of 17 (16.5%) patients reoccluded across all doses administered. There was no significant relationship between the maintenance dose rate and the incidence of reocclusion. However, there was strong association between total dose of rt-PA administered and the incidence (16%) of serious or life-threatening bleeding exclusive of surgery. Other factors associated with serious bleeding included low body weight, female gender, and total duration of rt-PA infusion. Reocclusion was independent of the 90-minute Thrombolysis in Myocardial Infarction trial perfusion grade and diameter of infarct vessel. Rethrombosis after establishment of early patency after rt-PA remains a significant problem that is unaffected by sustained rt-PA infusion in doses that can be tolerated.