Frank Vermeer

Long-term benefit of early thrombolytic therapy in patients with acute myocardial infarction: 5 year follow-up of a trial conducted by the Interuniversity Cardiology Institute of the Netherlands

Patients (n = 533) who participated in the Interuniversity Cardiology Institute of the Netherlands Trial were followed up for 3 to 7 years. The 5 year survival rate after thrombolytic therapy with intracoronary streptokinase was 81% (269 patients) compared with 71% after conventional therapy (264 patients). The greatest improvement in survival was observed in patients with anterior infarction (81% versus 64% with thrombolytic therapy or conventional therapy, respectively), in those with heart failure on admission or a previous infarction and in those with extensive myocardial ischemia on admission. Left ventricular ejection fraction at the time of hospital discharge was better after thrombolytic therapy. In the hospital survivors, long-term outcome was related to left ventricular function at the time of discharge and, to a lesser extent, to the underlying coronary artery disease. The initial therapy (thrombolysis or conventional) was not an independent additional determinant of long-term survival when left ventricular function and coronary status at the time of hospital discharge were taken into account. Thus, the salutary effects of thrombolytic therapy appear to be the result of myocardial salvage. Reinfarction within 3 years was observed more frequently after thrombolytic therapy, particularly in patients with inferior wall infarction and those with greater than or equal to 90% stenosis of the infarct-related vessel at discharge. Coronary bypass surgery and coronary angioplasty were performed more frequently after thrombolytic therapy than in conventionally treated patients. At 5 years, approximately 40% of patients in both groups had an uneventful course without reinfarction or additional revascularization procedures. These observations demonstrate that the benefits of thrombolytic therapy are maintained throughout 5 years of follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

Did prognosis after acute myocardial infarction change during the past 30 years? A meta-analysis

Much effort has been spent to improve survival after acute myocardial infarction. To investigate how effective this effort has been, a meta-analysis was performed of studies published between 1960 and 1987 concerning mortality after acute myocardial infarction. Thirty-six studies were analyzed. They were classified with respect to deaths in the hospital and at 1 month and the 5-year mortality rate starting at hospital discharge. Mortality was assessed from all studies by comparing studies from different institutions with use of identical inclusion criteria (externally controlled studies) and by analyzing studies reporting on changes in mortality in two or more comparable patient cohorts admitted to the same institution at different time periods (internally controlled studies). Reports on clinical trials (for example, thrombolytic therapy, beta-adrenergic blockade) in acute myocardial infarction were excluded. Average overall in-hospital mortality decreased from 29% during the 1960s to 21% during the 1970s and to 16% during the 1980s. The externally controlled studies also showed a declining trend: from 1960 to 1969, 32%, from 1970 to 1979, 19% and from 1980 to 1987, 15%. The 1-month overall mortality rate decreased from 31% during the 1960s to 25% during the 1970s and 18% during the 1980s externally controlled studies. Most internally controlled studies also showed significant improvement in in-hospital and 1-month survival. In contrast, 5-year mortality after hospital discharge did not significantly decrease (33% from 1960 to 1969 and 33% from 1970 to 1979). It is concluded that in the prethrombolytic era, short-term prognosis after acute myocardial infarction has improved since 1960.(ABSTRACT TRUNCATED AT 250 WORDS)

Relation between infarct size and left ventricular performance assessed in patients with first acute myocardial infarction randomized to intracoronary thrombolytic therapy or to conventional treatment

Reperfusion of ischemic myocardium has been reported to increase the cumulative creatine kinase activity in plasma per gram of infarcted myocardium as assessed with the method of Shell et al. In an attempt to find out whether infarct size assessment using the method of Witteveen et al was affected by reperfusion, the relation between enzymatic infarct size was analyzed using Witteveens method and left ventricular (LV) function parameters in 266 patients with first acute myocardial infarction randomized to intracoronary thrombolysis (n = 134) or conventional therapy (n = 132). Compared with patients allocated to conventional therapy, patients allocated to intracoronary thrombolysis had smaller enzymatic infarct size by 29% (p less than 0.001), smaller LV end-diastolic and end-systolic volume indexes by 10% (p less than 0.05) and 20% (p less than 0.005), respectively, and higher LV ejection fraction (55 +/- 1% vs 49 +/- 1%; p less than 0.001). The beneficial effects of thrombolytic therapy on LV performance were closely associated with thrombolysis-induced limitation of infarct size. The dependence from infarct size of LV end-diastolic volume, LV end-systolic volume, and ejection fraction was not different in the 2 therapy groups. It was concluded that Witteveens method of infarct size assessment is not influenced by the presence of reperfusion. Therefore, this method was recommended for trials on recanalization in patients with acute myocardial infarction.

Value of admission electrocardiogram in predicting outcome of thrombolytic therapy in acute myocardial infarction: a randomized trial conducted by the Netherlands interuniversity cardiology institute

To determine the value of the admission 12-lead electrocardiogram to predict infarct size limitation by thrombolytic therapy, data were analyzed in 488 of 533 patients with acute myocardial infarction (AMI) from a randomized multicenter study. All patients had typical electrocardiographic changes diagnostic for an AMI and were admitted within 4 hours after the onset of chest pain; 245 patients were allocated to thrombolytic treatment and 243 to conventional treatment. Cumulative 72-hour release into plasma of myocardial alpha-hydroxybutyrate dehydrogenase (HBDH) was used as a measure of infarct size. In general, the amount of infarct limitation due to thrombolytic therapy was proportional to the size of the area at risk. Patients with new Q waves, high QRS score and high ST-segment elevation or depression had the largest enzymatic infarct size in both treatment groups, irrespective of location of the AMI. Compared with conventionally treated patients, patients with anterior AMI treated with streptokinase had significant infarct size limitation (480 U/liter HBDH, 37%), and limitation was most prominent in those with Q waves (820 U/liter HBDH) or high ST elevation (750 U/liter HBDH). Infarct size limitation in inferior AMI was less impressive (330 U/liter HBDH, 33%) and patients with high ST-segment elevation (460 U/liter HBDH) or marked contralateral ST-segment depression (430 U/liter HBDH) had the most notable infarct limitation.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of a weight-adjusted single-bolus plasminogen activator in patients with myocardial infarction: A double-blind, randomized angiographic trial of lanoteplase versus alteplase

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.

Value of admission electrocardiogram in predicting outcome of thrombolytic therapy in acute myocardial infarction

To determine the value of the admission 12-lead electrocardiogram to predict infarct size limitation by thrombolytic therapy, data were analyzed in 488 of 533 patients with acute myocardial infarction (AMI) from a randomized multicenter study. All patients had typical electrocardiographic changes diagnostic for an AMI and were admitted within 4 hours after the onset of chest pain; 245 patients were allocated to thrombolytic treatment and 243 to conventional treatment. Cumulative 72-hour release into plasma of myocardial alpha-hydroxybutyrate dehydrogenase (HBDH) was used as a measure of infarct size. In general, the amount of infarct limitation due to thrombolytic therapy was proportional to the size of the area at risk. Patients with new Q waves, high QRS score and high ST-segment elevation or depression had the largest enzymatic infarct size in both treatment groups, irrespective of location of the AMI. Compared with conventionally treated patients, patients with anterior AMI treated with streptokinase had significant infarct size limitation (480 U/liter HBDH, 37%), and limitation was most prominent in those with Q waves (820 U/liter HBDH) or high ST elevation (750 U/liter HBDH). Infarct size limitation in inferior AMI was less impressive (330 U/liter HBDH, 33%) and patients with high ST-segment elevation (460 U/liter HBDH) or marked contralateral ST-segment depression (430 U/liter HBDH) had the most notable infarct limitation.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Argatroban and Alteplase in Patients with Acute Myocardial Infarction: The ARGAMI Study

ARGAMI was designed to assess safety and efficacy of argatroban compared with heparin as adjunctive treatment to alteplase in the treatment of patients with acute myocardial infarction. ARGAMI consisted of an open-dose finding study (35 patients) followed by a placebo-controlled study with double dummy technique and 2:1 (argatroban:heparin) randomization. An argatroban dosage of 100 μg/kg bolus plus 3 μg/kg/min infusion for 72 hours was selected for the randomized study in which 82 patients were allocated to argatroban and 45 to heparin (5000 U intravenous bolus, 1000 U/h infusion). Patency of the infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3 flow) after 90 minutes was obtained in 62 patients (76%) allocated to argatroban versus 37 patients (82%) allocated to heparin (p=ns). Angiograms after 24 hours and 5 to 10 days showed low reocclusion rates in both groups. Bleeding complications were observed in 16 patients allocated to argatroban (19.5%) and in 9 patients allocated to heparin (20.0%). One patient allocated to heparin suffered from hemorrhage stroke. Argatroban, given as adjunctive treatment to alteplase, is tolerated well in patients with acute myocardial infarction. Safety and efficacy of the combination alteplase and argatroban (with this dose regimen) are similar to those of alteplase and heparin.

Comparison of Saruplase and Alteplase in Acute Myocardial Infarction

Four hundred seventy-three patients with acute myocardial infarction (AMI) were treated with either saruplase (80 mg/hour, n = 236) or alteplase (100 mg every 3 hours, n = 237). Comedication included heparin and acetylsalicylic acid. Angiography was performed at 45 and 60 minutes after the start of thrombolytic therapy. When flow was insufficient, angiography was repeated at 90 minutes. Coronary angioplasty was then performed if Thrombolysis In Myocardial Infarction (TIMI) trial 0 to 1 flow was seen. Control angiography was at 24 to 40 hours. Baseline characteristics were similar. Angiography showed comparable and remarkably high early patency rates (TIMI 2 or 3 flow) in both treatment groups: at 45 minutes, 74.6% versus 68.9% (p = 0.22); and at 60 minutes 79.9% versus 75.3% (p = 0.26). Patency rates at 90 minutes before additional interventions were also comparable (79.9% and 81.4%). Angiographic reocclusion rates were not significantly different: 1.2% versus 2.4% (p = 0.68). After rescue angioplasty, angiographic reocclusion rates of 22.0% and 15.0% were observed. Safety data were similar for both groups. Thus, (1) early patency rates were high for saruplase and alteplase treatment, (2) reocclusion rates for both drugs were remarkably low, and (3) complication rates were similar. Thus, saruplase seems to be as safe and effective as alteplase.

Early referral for intentional rescue PTCA after initiation of thrombolytic therapy in patients admitted to a community hospital because of a large acute myocardial infarction

BACKGROUND If no in-house facilities for percutaneous transluminal coronary angioplasty (PTCA) are present, thrombolytic therapy is the treatment of choice for acute myocardial infarction (AMI). A few studies have shown benefit from rescue PTCA in patients directly admitted to centers with PTCA facilities. The obvious question arises whether patients with AMI initially admitted to a community hospital can benefit from early transfer for intentional rescue PTCA. METHODS AND RESULTS One hundred sixty-five patients were transferred early for intentional rescue PTCA from a community hospital at a distance of 20 miles. On arrival at the angioplasty center, bedside markers were used to determine reperfusion. In case of obvious reperfusion, no invasive procedure was done; otherwise, coronary angiography and rescue PTCA, if necessary, was performed. During transfer, 1 (1%) patient died and 15 (9%) patients had arrhythmic or hemodynamic problems. Median time delay between onset of chest pain and arrival at the community hospital and the PTCA center was 61 minutes (range 0 to 413) and 150 minutes (range 28 to 472), respectively. In 66 (40%) patients, reperfusion was diagnosed by noninvasive reperfusion criteria on arrival at the PTCA center (group 1). Ninety-eight (59%) patients without evident noninvasive criteria of reperfusion underwent angiography 187 median minutes after the onset of chest pain. Forty-one (25%) patients had Thrombolysis In Myocardial Infarction grade 3 flow, and no further intervention was performed (group 2). In the remaining 57 (35%) patients, rescue PTCA was performed, which was successful in 96% (group 3). In-hospital mortality rate was lowest in group 1 compared with the other 2 groups (0% vs 7% vs 11%; P <.05). Reinfarction was highest in group 1 compared with the other groups (17% vs 5% vs 2%; P <.01). No significant differences were found in coronary artery bypass grafting, stroke, or bleeding complications. The 1-year follow-up data showed low revascularization rates; 2 (1%) patients died after discharge from the hospital. CONCLUSIONS Early transfer of patients with large AMI for intentional rescue PTCA can be done with acceptable safety and is feasible within therapeutically acceptable time limits and results in additional early reperfusion in 33% of patients. A large, randomized, multicenter trial is needed to compare efficacy of intravenous thrombolytic treatment in a community hospital versus early referral for either rescue or primary PTCA.