Quantitative and qualitative effects of intracoronary streptokinase in unstable angina and non-Q wave infarction

Thrombolytic therapy has been shown to be effective in reopening totally occluded arteries in acute myocardial infarction. Coronary thrombus is also believed to play a role in the pathophysiology of unstable angina and non-Q wave infarction. However, few patients with these two acute coronary syndromes have been treated with intracoronary streptokinase. Therefore, 100,000 to 300,000 IU (mean 177,000 +/- 80,000 IU) of intracoronary streptokinase was infused into 36 consecutive catheterized patients who either presented with an acute episode of unstable angina or had had a recent non-Q wave infarction and in whom a less than 100% occluded ischemia-producing artery could be identified. Qualitative techniques utilizing vessel magnification and quantitative analysis with digital subtraction were performed on the ischemia-producing coronary lesion before and immediately after streptokinase therapy and 3 to 10 days later in 18 patients who were restudied at the time of transluminal coronary angioplasty. Before streptokinase treatment, 24 (67%) of 36 ischemia-producing arteries contained eccentric, irregular lesions. The percent diameter stenosis and percent area stenosis in all ischemia-producing arteries averaged 83.8 +/- 8.3% and 94.8 +/- 3.3%, respectively. After streptokinase treatment there were 23 arteries (64%) with eccentric irregular lesions. The percent diameter stenosis and percent area stenosis in all ischemia-producing arteries were similar to pre-streptokinase values (82.9 +/- 5.9% and 93.8 +/- 4.0%, respectively). At restudy, there were also no significant changes in any quantitative or qualitative variable. Five individual patients showed a significant reduction in percent stenosis after streptokinase. This improvement was independent of duration of symptoms, use of heparin before angiography, streptokinase dose or reduction of fibrinogen levels post-streptokinase. Two additional patients deteriorated clinically and developed total occlusion of the ischemia-producing artery within 12 hours of streptokinase infusion. These data suggest that intracoronary streptokinase may be of limited utility in either unstable angina or recent non-Q wave infarction with a less than 100% occluded ischemia-producing artery. In these syndromes, thrombus may be organized or short infusions may be given too late to be effective. In some cases, thrombus may even be absent. Whether longer infusion of streptokinase or other thrombolytic agents will be of benefit remains to be determined.     

Systemic versus intracoronary streptokinase infusion in the treatment of acute myocardial infarction

Clinically encouraging results can be obtained with an intravenous high dose short-time infusion of streptokinase in patients with evolving myocardial infarction. The feasibility and efficacy of the intracoronary and the systemic approach of streptokinase therapy in acute myocardial infarction are discussed in this report and include topics such as infarct artery recanalization success rate, coronary thrombus lysis time, benefit for patients with subtotal coronary occlusion, reocclusion rate, the necessity of additional surgical interventions, salvage of ischemic myocardium and side effects. The value of high dose intravenous short-time streptokinase infusion needs to be assessed with properly designed clinical trials against the background afforded by the results observed with direct intracoronary streptokinase infusion.     

Development and Pathophysiological Basis of Thrombolytic Therapy in Acute Myocardial Infarction Part II. 1977-1980 The Pathogenetic Role of Thrombus Is Established by the Goettingen Pilot Studies of Mechanical Interventions and Intracoronary Thrombolysis in Acute Myocardial Infarction

Between 1977 and 1980, our group performed immediate coronary angiography in 158 patients admitted with acute myocardial infarction (MI) at the University of Goettinger, Germany. From June 1978 to May 1979, our pioneering study of mechanical transcatheter recanalization of acute total coronary artery occlusions using guidewires and tapered catheters was performed. Restoration of antegrade flow in 7 of 13 patients was associated with an improvement in left ventricular function not seen in historical controls. From June 1979 to December 1980, the pathogenetic role of thrombus and spasm in acute coronary syndromes was explored in our pioneering study of intracoronary streptokinase infusion. Following injection of nitroglycerin, streptokinase was selectively infused at a rate of 2000 U/minute for 50–95 minutes. Only four of the initial 22 infarct patients showed improvement of antegrade flow following intracoronary nitroglycerin alone. Reopening of the completely obstructed vessel or increase in lumen diameter at the site of subtotal occlusion occurred in 22 of 29 infarct patients within 15–90 minutes of streptokinase infusion but in none of the five patients with unstable angina. Chest pain was alleviated and left ventricular function was improved significantly after successful lysis. The first presentation of both our mechanical and pharmacological interventions in acute MI to a large international audience at the annual American Heart Association meeting in 1979 convinced clinicians of the etiologic role of fibrin-rich coronary thrombus in acute MI. The demonstration of rapid restoration of antegrade flow initiated a worldwide renaissance in the application of thrombolytic therapy and paved the way for primary angioplasty in acute MI.     

Early cardiac catheterisation and coronary angiography in acute myocardial infarction

79 consecutive patients with documented acute myocardial infarction were admitted. 29 of these patients underwent early cardiac catheterisation, coronary arteriography and intracoronary streptokinase injection usually in response to post-myocardial infarction angina. Satisfactory reperfusion occurred in 80% of the patients with the least morbidity and mortality rate compared with medically anticoagulation treated group. 32 patients underwent elective catheterisation and coronary angiography between 1-16 days (average 7.6 days). 18 patients were not catheterised at all. This study evaluates our results of early thrombolytic, angioplastic or surgical revascularisation, and reviews the risk benefit value of early cardiac catheterisation and coronary angiography in patients with acute myocardial infarction.     

Intracoronary thrombolysis 3 to 13 days after acute myocardial infarction for postinfarction angina pectoris

The restoration of anterograde coronary flow long after coronary thrombosis may be of benefit to patients with continuing ischemia. To determine whether “old” intracoronary thrombi are susceptible to lysis with thrombolytic agents, 18 patients with angina at rest during evolving acute myocardial infarction (AMI) and total occlusion of the infarct vessel were treated with Intracoronary streptokinase 3 to 13 days after onset of AMI. In 12 of the 18 patients (67%), successful recanalization of the artery was achieved 6.9 ± 2.7 days after AMI. Thrombolysis was followed by coronary angioplasty in 2 patients. To evaluate the efficacy of this approach in reducing post-AMI Ischemia, the number of episodes of angina at rest was compared in patients with successful and unsuccessful attempts at recanalization. Even in patients without angioplasty, the mean number of daily episodes decreased from 1.02 ± 0.6 to 0.09 ± 0.2 in patients In whom reperfusion was achieved, and from 1.07 ± 0.8 to 0.88 ± 0.8 in those in whom it was not (p = 0.027 for the difference between the groups). Thus, in patients with early post-AMI angina, intracoronary streptokinase can restore flow in the occluded artery, may decrease the frequency of angina, and allows angioplasty to be performed.     

Role of intracoronary thrombus in acute complications during percutaneous transluminal coronary angioplasty

Coronary angiograms from 2,372 consecutive patients who underwent percutaneous transluminal coronary angioplasty (PTCA) were retrospectively reviewed for the presence of intracoronary thrombus (ICT) before dilatation. Patients with evolving acute myocardial infarction and those receiving thrombolytic therapy were excluded from analysis. Coronary artery thrombus was present in 126 patients (6%) (group 1). When compared to 2,246 patients (group 2) without ICT, group 1 had a higher incidence of unstable angina, 74% vs. 66% (less than 0.06), previous myocardial infarction, 59% vs. 37% (P less than .0001), and history of a recent myocardial infarction, 28% vs. 9% (P less than .0001). Patients with predilatation intracoronary thrombus had a higher risk for acute occlusion, 6% vs. 2% (P less than .002); however, the incidence of emergency coronary bypass surgery and myocardial infarction was similar in both groups. Therefore, the presence of predilatation intracoronary thrombus heralds an increased risk of acute occlusion, but not myocardial infarction or emergency coronary artery bypass surgery.     

Thrombolysis in postinfarction angina

Postinfarction angina carries a poor prognosis, with a 20-70% incidence of recurrent myocardial infarction (MI) or death within the subsequent 3-6 months. The pathophysiologic mechanisms causing postinfarction angina may include thrombus, complex coronary arterial lesions that form a nidus for thrombus formation, inadequate collateral supply following acute MI, or intimal endothelial dysfunction. The role of thrombus has been established in the pathophysiology of Q-wave MI, and thrombolytic treatment of patients presenting with acute transmural MI has been shown to salvage left ventricular function and to reduce mortality. However, thrombolytic therapy for the acute MI does not reduce the incidence of recurrent ischemia or infarction, as is evident from the 18-26% incidence of recurrent ischemia reported in the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) and Thrombolysis in Myocardial Infarction (TIMI) trials. In the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI) study the incidence of reinfarction was documented as 4% in the streptokinase group, which was actually significantly greater than in the placebo group (2%). In a randomized placebo-controlled study of thrombolysis for postinfarction angina, 29 patients were randomized to placebo (P group, n = 17) or to thrombolytic therapy (T group, n = 12). Patient groups were similar with respect to age, location of MI, ejection fraction, severity of coronary artery disease, and antianginal therapy. Patients underwent coronary angiography 6 +/- 1 days postinfarction. Filling defects consistent with intracoronary thrombus was seen in 11 of 12 T group patients and in 11 of 17 P group patients prior to treatment. Lysis occurred in 7 of 11 T patients and 1 of 11 P (p less than 0.02). Holter-detected silent ischemia was compared pre- and posttherapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Emergency coronary artery bypass surgery after intracoronary thrombolysis for evolving myocardial infarction.

Sixteen patients underwent emergency coronary artery bypass surgery immediately after intracoronary streptokinase infusion for acute evolving myocardial infarction. Of these, 11 patients had 70% residual stenosis in the recanalised vessel, and in five thrombolysis was unsuccessful. There were no hospital deaths. All the patients sustained myocardial necrosis, the peak activity of creatine phosphokinase correlating with the time to reperfusion. Chest tube drainage (mean 960 ml) was significantly higher than for control patients but did not correlate with the total dosage of streptokinase. No patients had further myocardial infarction or developed recurrent angina. Selected patients may benefit from coronary bypass surgery after intracoronary streptokinase infusion. If necessary this may be performed immediately with low mortality and morbidity.     

Emergency coronary artery bypass surgery after intracoronary thrombolysis for evolving myocardial infarction

Sixteen patients underwent emergency coronary artery bypass surgery immediately after intracoronary streptokinase infusion for acute evolving myocardial infarction. Of these, 11 patients had 70% residual stenosis in the recanalised vessel, and in five thrombolysis was unsuccessful. There were no hospital deaths. All the patients sustained myocardial necrosis, the peak activity of creatine phosphokinase correlating with the time to reperfusion. Chest tube drainage (mean 960 ml) was significantly higher than for control patients but did not correlate with the total dosage of streptokinase. No patients had further myocardial infarction or developed recurrent angina. Selected patients may benefit from coronary bypass surgery after intracoronary streptokinase infusion. If necessary this may be performed immediately with low mortality and morbidity.     

Successful result from delayed streptokinase administration: subtotal thrombotic occlusion in a subsequently normal coronary artery

This report describes successful results from intracoronary streptokinase administered beginning 6 hr after onset of symptoms to a 32-year-old male with subtotal vessel occlusion by thrombus. Coronary angiography 26 days later demonstrated normal vessels. We conclude that 1) duration of symptoms beyond 3-4 hr should not preclude the use of thrombolytic therapy in evolving myocardial infarction, 2) this patient exemplifies the higher incidence of subsequently demonstrated normal coronary arteries in patients under age 35 with acute myocardial infarction; arterial spasm and platelet aggregation are the most likely causes of coronary occlusion in these patients.     

Use of a new thrombus extraction catheter (the Pronto) in the treatment of acute myocardial infarction

The finding of an intracoronary thrombus at the time of coronary angiography is common in patients presenting with an acute coronary syndrome. Pharmacologic and mechanical treatment strategies have been developed and reported to facilitate the treatment of the thrombus along with a percutaneous coronary intervention. We report a case in which a Pronto thrombectomy catheter was utilized to facilitate thrombus removal prior to the placement of a coronary stent in a patient who developed postinfarct angina and pulmonary edema after successful thrombolytic therapy for a acute ST segment elevation myocardial infarction.     

Thrombosis and thrombolysis in unstable angina

Pathophysiology of unstable angina involves spasm, plaque rupture, activation of platelets, and coagulation. The incidence and frequency of intracoronary thrombus formation are presently under active assessment in order to establish the potential benefit of thrombolytic therapy. A preliminary study was conducted in patients admitted in our coronary care unit for unstable angina with typical clinical and electrocardiographic criteria and with early coronary angiogram. After exclusion of 4 patients with left main coronary stenosis or contraindications for thrombolysis, 16 patients received thrombolytic infusion and 14 underwent a second coronary angiogram. Seven patients had an intracoronary thrombus (6 nonocclusive, 1 occlusive) and at the second angiogram only 3 nonocclusive thrombi were modified (1 disappeared, 2 were reduced). Moreover, the quantitative Coronary Angiography Analysis System (CAAS) in the 11 cases suitable for analysis did not show any significant changes, especially in the Ambrose type IIB lesions. In-hospital clinical outcome was not influenced by thrombolytic therapy (5 ischemic recurrences, 1 fatal myocardial infarction, 4 emergency and 4 elective revascularization procedures). This short series is in agreement with the literature data. Only one third of patients with active unstable angina remains refractory to conventional therapy. The transient benefit of thrombolysis is limited to patients with demonstrated intracoronary thrombi. Clinical or angiographic improvement are not always in correlation and until now do not seem able to prevent short-term recurrences or the need for revascularization procedures.     

Effects of thrombolytic therapy in unstable angina: clinical and angiographic results

The incidence of intracoronary thrombus and the effects of thrombolytic therapy were studied in 41 patients with unstable angina. All patients underwent coronary angiography 2 to 69 h (mean 19) after their last attack of chest pain. Immediately after angiography, 21 patients received intracoronary streptokinase (250,000 IU in 45 min) and were retrospectively analyzed. Twenty patients received intravenous recombinant tissue-type plasminogen activator (rt-PA) (100 mg in 3 h) and were involved in a prospective study. Eleven of the 21 patients from the streptokinase group and 11 of the 20 patients from the rt-PA group showed a decrease in the severity of the coronary stenosis on repeat angiography 1 day later. A decrease in coronary obstruction was primarily observed in 10 of 13 patients with a complete stenosis and in 6 of 9 patients with a subtotal stenosis and markedly diminished coronary flow. Improvement in coronary anatomy was not determined by the clinical characteristics of the patients. Twenty-eight of the 41 patients had angiographic evidence of intracoronary thrombus formation before and 16 had such evidence after thrombolytic treatment. Nine patients developed a small increase in serum cardiac enzymes before or during treatment. Ischemic symptoms and the incidence of surgical or angioplastic intervention were not different in patients with or without a reduction in coronary artery stenosis after fibrinolytic therapy. These observations suggest a high incidence of coronary thrombosis in patients with unstable angina. The data do not permit assessment of the clinical therapeutic efficacy of thrombolytic therapy. Better risk stratification and placebo-controlled prospective studies are required to obtain information on the risk/benefit ratio of such therapy in unstable angina.     

Myocardial infarction management with peripheral streptokinase

The early management of myocardial infarction (MI) is undergoing a new evolution. Aggressive treatment and new invasive modalities have brought improved prognosis to these patients. Intracoronary administration of fibrinolytic agents is rapidly gaining wide acceptance. We report a pilot protocol for administration of peripheral intravenous (IV) versus direct intracoronary fibrinolytic agents in acute MI. Thirty patients with acute evolving MI were assigned consecutively to receive fibrinolytic therapy; 15 patients received intracoronary streptokinase and 15 received peripheral IV streptokinase at a dosage of 1.5 million units over a 30-minute period. Evaluation by clinical symptoms, ECG changes, and hemodynamic studies by angiography and radionuclide ventriculography indicated comparable and beneficial results for both groups. Patients assigned to the IV therapy were able to receive streptokinase therapy 1.5 hours earlier than those receiving intracoronary therapy, and they had a higher incidence of reperfusion. We conclude that IV streptokinase therapy may be preferable to intracoronary therapy in view of a higher reperfusion frequency, fewer complications, and greater ease of administration. With both treatment modalities, comparable improvement in left ventricular function was noted. Institutions that do not have invasive techniques available may well be the first to benefit from this method of myocardial salvage, and we encourage cooperation between emergency and cardiology departments.     

Reperfusion arrhythmia: a marker of restoration of antegrade flow during intracoronary thrombolysis for acute myocardial infarction

We studied the effects of coronary recanalization on arrhythmogenesis in patients undergoing intracoronary thrombolysis during the early hours of myocardial infarction. Catheterization, ventriculography, coronary angiography, and intracoronary streptokinase infusion were performed in 22 patients. Twenty-one of 22 had thrombotic total occlusion of the infarct-related transient thrombolysis with reocclusion by the end of the procedure. In 12 of these 17 patients, restoration of antegrade coronary flow was accompanied by transient arrhythmia. In these 12 patients coronary angiography within seconds of onset of arrhythmia showed vessel patency in a previously totally occluded coronary artery. Two additional patients developed arrhythmias during streptokinase infusion but after reperfusion had already been established. Accelerated idioventricular rhythm was most often noted. Sinus bradycardia and atrioventricular block with hypotension occurred during restoration of flow in arteries supplying the inferoposterior left ventricle. These arrhythmias may be useful noninvasive markers of successful reperfusion during thrombolytic therapy in acute myocardial infarction.     

Relation of effectiveness of intracoronary thrombolysis in acute myocardial infarction to systemic thrombolytic state

Twenty-nine patients received intracoronary thrombolytic therapy for acute myocardial infarction 3.5 +/- 1.4 hours (mean +/- standard deviation) after the onset of pain. Ten patients received urokinase (UK) and 19 patients received streptokinase (SK). Laboratory variables of the coagulation system were measured before and immediately after therapy. When comparing patients in whom coronary artery recanalization occurred vs those in whom the artery remained occluded, those in whom recanalization was achieved had greater alterations in fibrinogen, prothrombin time, activated partial thromboplastin time, fibrin/fibrinogen degradation products and plasminogen by thrombolytic therapy than did those in whom recanalization was not achieved (p less than 0.05 for all variables). Euglobulin lysis time showed a similar but nonsignificant trend (p = 0.114). Patients who received SK showed markedly greater alterations in coagulation parameters than did patients treated with UK (p less than 0.05 for 5 of 6 variables measured) and had a much higher incidence of successful thrombolysis (74% for SK, 20% for UK). These data indicate that the development of a systemic fibrinolytic state contributes to success when using intracoronary thrombolytic agents in acute myocardial infarction. Rather than being considered an adverse effect of therapy, a systemic lytic state may serve as a reasonable clinical goal in attempting to produce thrombolysis.     

Combination therapy for evolving myocardial infarction: Intracoronary thrombolysis and percutaneous transluminal angioplasty

Nonsurgical coronary reperfusion for evolving myocardial infarction is a promising new technique for the salvage of jeopardized myocardium. Successful reperfusion can be established by intracoronary infusion of streptokinase in approximately 75 percent of patients within the first 6 hours of transmural infarction [1,2]. Following recanalization, most patients are left with high grade fixed coronary stenoses which are potential sites for recurrent thrombus formation. Since the underlying site for coronary thrombosis is still present, reocclusion may occur. Indeed, early experience suggests that recurrence of thrombosis is not uncommon [3,4]. Therapy for evolving myocardial infarction should, in some patients, involve not only thrombolysis, but also an attack on the fixed coronary lesion. We describe a patient with evolving myocardial infarction who was treated successfully with combination therapy consisting of intracoronary streptokinase followed by percutaneous transluminal coronary angioplasty [5].     

Intracoronary thrombolytic treatment: another hazard

A patient with acute anterior myocardial infarction was treated with intracoronary thrombolysis. At cardiac catheterisation the first contrast injection into the left coronary artery dislodged some of the thrombus occluding the left anterior descending coronary artery. The thrombus embolised into the circumflex artery where fortunately it fragmented without causing occlusion. The risk of detachment of thrombus should be borne in mind when angiography and thrombolytic treatment are considered in acute myocardial infarction.     

Intracoronary thrombolytic treatment: another hazard.

A patient with acute anterior myocardial infarction was treated with intracoronary thrombolysis. At cardiac catheterisation the first contrast injection into the left coronary artery dislodged some of the thrombus occluding the left anterior descending coronary artery. The thrombus embolised into the circumflex artery where fortunately it fragmented without causing occlusion. The risk of detachment of thrombus should be borne in mind when angiography and thrombolytic treatment are considered in acute myocardial infarction.     

Pathogenesis of impending myocardial infarction and acute myocardial infarction: clinical and angiographic evaluation of coronary thrombosis as a precipitating factor

In order to investigate the role of coronary thrombosis as a precipitating factor of acute myocardial infarction (AMI), we examined coronary angiographic findings in 89 patients with AMI taken within 24 hours of the onset and in 42 patients with prolonged angina attack of impending myocardial infarction (impending MI) taken within 50 hours of the last angina attack. Furthermore, in the patients with impending MI, the effects of intracoronary and intravenous thrombolytic therapy and anticoagulant therapy used to prevent impending MI from developing into AMI, were also studied. (1) In 72 of 89 patients (81%) with AMI, coronary thrombi were detected angiographically. The thrombi were detected most frequently (88%) in angiographs taken within 3 hours of onset. (2) In 23 of 42 patients with impending MI, coronary thrombi were detected angiographically. In 6 patients with coronary thrombi who underwent intracoronary thrombolysis during angina attack, occlusive coronary thrombi in ischemia-related vessels were the observed, and recanalization by thrombolysis with intracoronary urokinase infusion relieved chest pain and improved ECG changes. (3) The incidence of AMI in 42 patients with impending MI who were treated with intracoronary and intravenous thrombolytic therapy and anticoagulant therapy was significantly less than in the conventional therapy group (80 patients) (11.9% vs. 27.5%; p less than 0.05). In 4 of 5 patients with developing AMI, coronary thrombi were detected angiographically in the acute phase of impending MI. These results indicate that coronary thrombosis plays an important role not only in the precipitation of impending MI but also in the development of impending MI to AMI.