Randomized trial of direct coronary angioplasty versus intravenous streptokinase in acute myocardial infarction

OBJECTIVES: The objective of this study was to obtain preliminary data on the relative clinical utility of direct coronary angioplasty compared with that of intravenous thrombolytic therapy for patients with acute myocardial infarction. BACKGROUND: The relative merits of intravenous thrombolytic therapy and direct coronary angioplasty as treatment for acute myocardial infarction are incompletely understood, and randomized trials of these treatments have been extremely limited. METHODS: One hundred patients with ST segment elevation presenting to a single high volume interventional center within 6 h of the onset of chest pain were randomized to receive either streptokinase (1.2 million U intravenously over 1 h) or immediate catheterization and direct coronary angioplasty. Patients were excluded for age > or = 75 years, prior bypass surgery, Q wave infarction in the region of ischemia or excessive risk of bleeding. All patients were then treated with aspirin (325 mg orally/day) and heparin (1,000 U intravenously/h) for 48 h until catheterization was performed to determine the primary study end point, namely, infarct-related artery patency at 48 h. Secondary end points were in-hospital death, left ventricular ejection fraction at 48 h and time to treatment. RESULTS: There was no difference in the baseline characteristics of the two treatment groups. Overall patient age was 56 +/- 10 years, 83% of patients were male, 11% had prior infarction, 40% had anterior infarction and 97% were in Killip class I or II. Although time to treatment was delayed in the angioplasty group (238 +/- 112 vs. 179 +/- 98 min, p = 0.005), there was no difference in 48-h infarct-related artery patency or left ventricular ejection fraction (patency 74% vs. 80%; ejection fraction 59 +/- 13% vs. 57 +/- 13%; angioplasty vs. streptokinase, p = NS for both). There were no major bleeding events, and the mortality rate with angioplasty (6%) and streptokinase (2%) did not differ (p = NS). CONCLUSIONS: These results suggest that intravenous thrombolytic therapy might be preferred over coronary angioplasty for most patients because of the often shorter time to treatment.     

Differential effects of tissue plasminogen activator and streptokinase on infarct size and on rate of enzyme release: influence of early infarct related artery patency. The GUSTO Enzyme Substudy

BACKGROUND: The recent international GUSTO trial of 41,021 patients with acute myocardial infarction demonstrated improved 90-min infarct related artery patency as well as reduced mortality in patients treated with an accelerated regimen of tissue plasminogen activator, compared to patients treated with streptokinase. A regimen combining tissue plasminogen activator and streptokinase yielded intermediate results. The present study investigated the effects of treatment on infarct size and enzyme release kinetics in a subgroup of these patients. METHODS: A total of 553 patients from 15 hospitals were enrolled in the study. Four thrombolytic strategies were compared: streptokinase with subcutaneous heparin, streptokinase with intravenous (i.v.) heparin, tissue plasminogen activator with i.v. heparin, and streptokinase plus tissue plasminogen activator with i.v. heparin. The activity of alpha-hydroxybutyrate dehydrogenase (HBDH) in plasma was centrally analysed and infarct size was defined as cumulative HBDH release per litre of plasma within 72 h of the first symptoms (Q(72)). Patency of the infarct-related vessel was determined by angiography in 159 patients, 90 min after treatment. RESULTS: Infarct size was 3.72 g-eq.1(-1) in patients with adequate coronary perfusion (TIMI-3) at the 90 min angiogram and larger in patients with TIMI-2 (4.35 g-eq.1(-1) or TIMI 0-1 (5.07 g-eq.1(-1) flow (P = 0.024). In this subset of the GUSTO angiographic study, early coronary patency rates (TIMI 2 + 3) were similar in the two streptokinase groups (53 and 46%). Higher, but similar, patency rates were observed in the tissue plasminogen activator and combination therapy groups (87 and 90%). Median infarct size for the four treatment groups, expressed in gram-equivalents (g-eq) of myocardium, was 4.4, 4.5, 3.9 and 3.9 g-eq per litre of plasma (P = 0.04 for streptokinase vs tissue plasminogen activator). Six hours after the first symptoms, respectively 5.3, 6.6, 14.0 and 13.6% of total HBDH release was complete (P < 0.0001 for streptokinase vs tissue plasminogen activator). CONCLUSIONS: Rapid and complete coronary reperfusion salvages myocardial tissue, resulting in limitation of infarct size and accelerated release of proteins from the myocardium. Treatment with tissue plasminogen activator, resulting in earlier reperfusion was more effective in reducing infarct size than the streptokinase regimens, which contributes to the differences in survival between treatment groups in the GUSTO trial.     

Randomized comparison of direct thrombin inhibition versus heparin in conjunction with fibrinolytic therapy for acute myocardial infarction: results from the GUSTO-IIb Trial. Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO-IIb) Investigators

OBJECTIVES: We sought to show that hirudin might interact differently with streptokinase (SK) and tissue-type plasminogen activator (t-PA), which could reduce the incidence of death or reinfarction at 30 days. BACKGROUND: In a large-scale trial of patients with acute coronary syndromes, hirudin provided modest benefit compared with heparin. However, the interaction with thrombolytic agents was not specifically assessed. METHODS: Patients with symptoms of acute myocardial infarction and electrocardiographic ST segment elevation were treated with thrombolytic therapy and randomly assigned to receive hirudin or heparin. RESULTS: A total of 2,274 patients received t-PA, and 1,015 received SK. Baseline characteristics were balanced by antithrombin assignment. Among SK-treated patients, death or reinfarction at 30 days occurred more often in those treated with adjunctive heparin (14.4%) rather than hirudin (8.6%, odds ratio [OR] 1.78, 95% confidence interval [CI] 1.20 to 2.66, p = 0.004). Among t-PA-treated patients, the rates were 10.9% with heparin and 10.3% with hirudin (OR 1.06, 95% CI 0.81 to 1.38, p = 0.68; for treatment heterogeneity: chi-square 4.20, degrees of freedom [df] 1, p = 0.04). After adjustment for baseline differences between thrombolytic groups, the rates were 9.1% for SK with hirudin, 10.3% for t-PA with hirudin, 10.5% for t-PA with heparin and 14.9% for SK with heparin (for treatment heterogeneity: chi-square 4.5, df 1, p = 0.03), suggesting that the beneficial treatment effect of hirudin was limited to the SK-treated patients. CONCLUSIONS: Hirudin interacts favorably with SK but not t-PA, highlighting the importance of thrombin activity after SK therapy and the potential for simulating the effects of a more potent fibrinolytic agent through direct antithrombin therapy.     

Pharmacologic profile of survivors of acute myocardial infarction at United States academic hospitals

Optimal drug therapy for patients with acute myocardial infarction (AMI) is well described in the medical literature. However, data on the actual pharmacologic management of patients surviving AMI at academic hospitals is unavailable. The purpose of this study was to document treatment profiles in 500 patients surviving AMI at 12 academic hospitals in the United States. These profiles were compared with established guidelines and were evaluated for trends. Overall, thrombolytics (streptokinase > or = tissue-type plasminogen activator) were administered in 29% of the patients, with a greater proportion of patients receiving beta-blockers than calcium channel antagonists in the initial 72 hours (61% vs 40%; p < 0.005) and at discharge (51% vs 35%; p < 0.005). Further, women were less likely than men to receive thrombolytic therapy (odds ratio [OR] = 0.61; confidence interval [CI], 0.54 to 0.69) or beta-blocker therapy within the first 72 hours (OR = 0.61; CI, 0.55 to 0.67) or at hospital discharge (OR = 0.53; CI, 0.48 to 0.58). Overall, improvements could still be made in the number of patients who receive thrombolytic and acute and chronic beta-blocker therapies after AMI, particularly in women. Changes in treatment profiles may be a reflection of the publication of large clinical trials.     

Ridogrel does not increase the speed and rate of coronary recanalization in patients with myocardial infarction treated with alteplase and heparin

Ridogrel, a compound with the dual property of inhibiting the synthesis of thromboxane and blocking the receptors of thromboxane/prostaglandin/endoperoxides, has been shown to accelerate the speed of recanalization and to delay or prevent reocclusion during systemic thrombolysis with tissue plasminogen activator in experimental animals. Ninety patients who had not taken any antiplatelet drugs within the last 10 days were randomized to either intravenous ASA 250 mg immediately before the thrombolytic treatment and 100 mg once a day orally thereafter or ridogrel 300 mg i.v. before thrombolytic treatment and 300 mg b.i.d. orally thereafter. All patients were given intravenous heparin concomitantly with alteplase. The patency of the infarct-related artery was determined by coronary angiography before the administration of the thrombolytic agent and by repeated coronary angiography every 15 min until the end of the administration of alteplase. A final angiogram was obtained 48 to 72 h later. At 90 min, the recanalization and patency rates were the same in the two treatment groups with no intergroup difference in the speed of recanalization.     

Use of allografts in knee reconstruction: II. Surgical considerations

This paper aims to review current literature on the treatment of acute intraventricular hemorrhage in adults with intraventricular infusion of fibrinolytic agents. A literature search on the topics of "intraventricular hemorrhage" or "intracerebral hemorrhage" with "thrombolytic therapy", "fibrinolytic therapy", "urokinase", "streptokinase", "tissue plasminogen activator" or "tPA" covering the years 1966-1997 was carried out electronically. This was supplemented by searching the reference lists of the identified articles. Articles regarding exclusively intracerebral hemorrhage or hematoma, neonatal intraventricular hemorrhage, non-therapeutic issues, and laboratory research were excluded. The included articles are summarized in evidence and evaluation tables. Six articles evaluating the treatment of intraventricular hemorrhage in adults with intraventricular fibrinolytic agents were identified. One reports a small randomized clinical trial including 16 patients and appears to show a statistically insignificant preference for urokinase treatment. Five other reports present case series for which a total of 58 patients were exposed to either streptokinase, urokinase, or recombinant tissue plasminogen activator (rt-PA) and suggest good outcome. Two of them were with non-randomized retrospective or prospective controls, and three have no controls. Despite important limitations, all reports suggest that blood is more rapidly cleared from the ventricles and outcome is better when administering a fibrinolytic agent intraventricularly. While the experience presented in these papers suggests that intraventricular administration of fibrinolytic agents may be associated with fewer complications, more rapid clearing of blood from the ventricles, less late hydrocephalus, and better long-term outcome than is seen in patients treated with ventricular drainage alone, it is insufficient to recommend such treatment as a matter of policy. Substantial methodologic flaws render these findings suggestive at best. If the suggestive findings of these studies were confirmed in well-designed randomized clinical trials, an important impact on clinical practice could be expected.     

Thrombolytic therapy compared with mechanical recanalization in non-acute peripheral arterial occlusions: a randomized trial

PURPOSE: To evaluate whether thrombolytic therapy followed by angioplasty has any added benefit compared with angioplasty alone for the treatment of chronic peripheral arterial occlusions. PATIENTS AND METHODS: Twenty patients with claudication or limb-threatening ischemia of at least 3 weeks duration due to iliac or femoropopliteal artery occlusions were randomized either to thrombolytic therapy with recombinant tissue-type plasminogen activator for up to 4 hours (n = 11) followed by angioplasty or to angioplasty alone (n = 9). Clinical follow-up was obtained for 1 year. RESULTS: Life-table analysis revealed a significant improvement in the cumulative primary patency rate for patients with claudication treated initially with thrombolysis followed by angioplasty (n = 7; 86% at 6 months; 51% at 1 year) compared with angioplasty alone (n = 9; 11% at 6 months and 1 year) (P < .02). All four patients with limb-threatening ischemia were randomized to thrombolytic therapy, and none exhibited continued patency at 1 year. The most common complication in the thrombolysis group was peripheral embolization; three of these four patients were among those who had limb-threatening ischemia as the indication for entry into this study. There was no increased incidence of bleeding with thrombolytic therapy. CONCLUSIONS: A short course of thrombolytic therapy prior to angioplasty appears to improve the 1-year patency rate for claudication due to iliac or femoropopliteal occlusions. However, patients with limb-threatening ischemia have a high prevalence of peripheral embolization and dismal patency rates with this form of therapy. A larger scale study is necessary to confirm these findings.     

ESPRIT: a European study of the prevention of reocclusion after initial thrombolysis with duteplase in acute myocardial infarction

BACKGROUND: The goal of thrombolytic treatment in acute myocardial infarction is reperfusion of the infarct-related coronary artery. Duteplase is a double-chain recombinant tissue-type plasminogen activator. Its efficacy and safety were evaluated in patients with acute myocardial infarction treated within 4 h of onset of chest pain in this multicentre, open, non-controlled trial. METHODS AND RESULTS: A total of 273 patients were enrolled and treated with duteplase 0.6 MU.kg-1 over 4 h, with concomitant oral aspirin and intravenous heparin. Coronary arteriography was performed at 60 min, 90 min and approximately 24 h after the start of duteplase infusion to assess the perfusion grade (TIMI scoring) of the infarct-related coronary artery. Safety was assessed by monitoring patients closely for bleeding and for all other adverse experiences during the 72-h study period. Reinfarction during the study period was also recorded, and deaths at any time during the period in hospital were documented. TIMI grade 2 or 3 patency of the infarct-related coronary artery at 90 min was achieved in 70% of the patients and 7% of these "patent' infarct-related coronary arteries had reoccluded by 20 to 36 h. Clinical reinfarction during the 72-h study period was observed in 7%. Total in-hospital mortality was 8%. Serious or life-threatening bleeding occurred in 4% of the patients. There was one haemorrhagic stroke, and this was fatal. CONCLUSIONS: Weight-adjusted duteplase infusion, together with oral aspirin and intravenous heparin, in acute myocardial infarction resulted in patency of the infarct-related coronary artery and a safety profile comparable to those reported for the other form of tissue-type plasminogen activator, alteplase. However, there remains a problem with reocclusion and reinfarction after initially successful thrombolysis.     

Does PTCA in acute myocardial infarction affect mortality and reinfarction rates? A quantitative overview (meta-analysis) of the randomized clinical trials

BACKGROUND: Percutaneous transluminal coronary angioplasty (PTCA) is often performed after acute myocardial infarction (AMI) either as an adjuvant to thrombolytic therapy or instead of thrombolysis. The effect of PTCA in AMI on mortality and reinfarction has remained unclear, with the available randomized trials indicating inconsistent results. METHODS AND RESULTS: A systematic overview (meta-analysis) of the randomized trials was conducted to assess the effect of PTCA in AMI on mortality and reinfarction rates. Data from 7 trials in which primary PTCA was evaluated and 16 trials in which PTCA after thrombolysis was studied were included in this overview, comprising a total of 8496 patient. The trials represented different approaches to the timing of PTCA after AMI. The trials of PTCA after thrombolytic therapy were also categorized according to the different protocols with respect to the routine or elective character of PTCA in the invasive group. A reduction in short-term (6 week) mortality (odds ratio, 0.56; 95% CI, 0.33, 0.94) and in the combined outcome of short-term mortality and nonfatal reinfarction (odds ratio, 0.53; 95% CI, 0.35, 0.80) was observed in the trials comparing primary PTCA with thrombolytic therapy. In contrast, in trials in which an approach of thrombolysis and PTCA was compared with thrombolytic therapy alone, there was no important difference in early mortality, with an apparent reduction in mortality between 6 and 52 weeks. The lower mortality between 6 and 52 weeks among 6-week survivors seemed to be restricted to the subgroup of trials in which PTCA was used as a routine strategy (odds ratio, 0.58; 95% CI, 0.39, 0.87). CONCLUSIONS: Although the analyses of the various categories of trials suggest that primary PTCA may be more beneficial than thrombolytic therapy in AMI, these data should be interpreted cautiously unless confirmed by larger studies. In contrast, the addition of various other strategies of PTCA to thrombolytic therapy does not convincingly indicate a clinically different outcome than if a more conservative strategy is followed, in which PTCA is used only if clinically indicated. Some specific strategies, however, such as rescue PTCA in high-risk patients with occluded arteries, may be of benefit.     

Treatment of hepatic venocclusive disease with recombinant human tissue plasminogen activator and heparin in 42 marrow transplant patients

The purpose of this report is to review the Fred Hutchinson Cancer Research Center experience of treating patients with venocclusive disease of the liver (VOD) after marrow transplantation using recombinant human tissue plasminogen activator (rh-tPA) and heparin. The charts of 42 patients who had received rh-tPA and heparin for the treatment of VOD between February 1991 and December 1995 were reviewed. Response to rh-tPA and heparin was defined as a reduction in total serum bilirubin by 50% within 10 days of starting treatment. Total serum bilirubin, percent weight gain, and serum creatinine before, after, and at the start of rh-tPA and heparin were examined to determine whether these laboratory values distinguished patients who responded to treatment from those who did not. We also evaluated whether evidence of multiorgan failure (requirement for supplemental oxygen, requirement for hemodialysis, requirement for mechanical ventilation) or whether the calculated probability of a fatal outcome from VOD could discriminate responders from nonresponders. In addition, the incidence and outcome of bleeding as a major complication of thrombolytic therapy was examined. Twelve patients responded to rh-tPA and heparin and 30 patients did not. There were no statistically significant differences between responders and nonresponders in the day treatment was started, dose of rh-tPA, total serum billirubin, and percent weight gain before, after, or at the start of treatment, or the calculated probability of dying from VOD on the day treatment with rh-tPA and heparin was begun. More nonresponding patients required dialysis or mechanical ventilation (11 of 30) before or at the start of rh-tPA and heparin than responding patients (0 of 12), P = .0183. Serum creatinine was greater at the start of treatment in nonresponding patients (1.9 +/- 1.3 mg/dL) than in responding patients (1.1 +/- 0.4 mg/dL), P = .0794. Ten patients had severe bleeding episodes, which resulted in death in three patients and may have contributed to death in an additional three patients. Treatment for VOD using rh-tPA and heparin was successful in 29% of patients but was associated with a significant risk of life-threatening hemorrhage. Requirement for supplemental oxygen, dialysis, or mechanical ventilation before the start of treatment were prognostic indicators of no response to thrombolytic therapy. We do not recommend treatment using tPA and heparin in patients with severe VOD who have already developed multiorgan dysfunction.     

TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: results of the TIMI 10B trial. Thrombolysis in Myocardial Infarction (TIMI) 10B Investigators

BACKGROUND: Bolus thrombolytic therapy is a simplified means of administering thrombolysis that facilitates rapid time to treatment. TNK-tissue plasminogen activator (TNK-tPA) is a highly fibrin-specific single-bolus thrombolytic agent. METHODS AND RESULTS: In TIMI 10B, 886 patients with acute ST-elevation myocardial infarction presenting within 12 hours were randomized to receive either a single bolus of 30 or 50 mg TNK-tPA or front-loaded tPA and underwent immediate coronary angiography. The 50-mg dose was discontinued early because of increased intracranial hemorrhage and was replaced by a 40-mg dose, and heparin doses were decreased. TNK-tPA 40 mg and tPA produced similar rates of TIMI grade 3 flow at 90 minutes (62.8% versus 62.7%, respectively, P=NS); the rate for the 30-mg dose was significantly lower (54.3%, P=0.035) and was 65. 8% for the 50-mg dose (P=NS). A prespecified analysis of weight-based TNK-tPA dosing using median TIMI frame count demonstrated a dose response (P=0.001). Similar dose responses were observed for serious bleeding and intracranial hemorrhage, but significantly lower rates were observed for both TNK-tPA and tPA after the heparin doses were lowered and titration of the heparin was started at 6 hours. CONCLUSIONS: TNK-tPA, given as a single 40-mg bolus, achieved rates of TIMI grade 3 flow similar to those of the 90-minute bolus and infusion of tPA. Weight-adjusting TNK-tPA appears to be important in achieving optimal reperfusion; reduced heparin dosing appears to improve safety for both agents. Together with the safety results from the parallel Assessment of the Safety of a New Thrombolytic: TNK-tPA (ASSENT I) trial, an appropriate dose of this single-bolus thrombolytic agent has been identified for phase III testing.     

Clinical trials of direct thrombin inhibitors in acute ischaemic syndromes

Unfractionated heparin is commonly used as standard therapy along with aspirin for the management of acute ischaemic syndromes. However, heparin has many limitations including a poor dose effect response and an inability to inactivate clot bound thrombin. Direct thrombin inhibitors inactivate clot bound thrombin and also prevent thrombin induced platelet aggregation. The prototypical direct thrombin inhibitor, hirudin, has been tested in the TIMI 9 and GUSTO II trials. These trials showed a 14% reduction in reinfarction at 30 days, but there was no effect on mortality or on the combined end point of death and nonfatal myocardial infarction (10.8% heparin versus 10.0% hirudin). More moderate bleeding occurred with hirudin than with intravenous heparin. Hirulog has been shown to increase the rate of TIMI grade 3 patency (from 35% to 48%, p = 0.03) at 90 minutes after streptokinase administration, and this is now being tested in a large mortality trial. Further trials are necessary to further test whether patient care can be improved by appropriate doses of these agents administered for an appropriate duration.     

A bleeding model in rabbits demonstrate fresh clot selectivity for a genetically engineered variant of tissue-type plasminogen activator and for streptokinase

The way in which three thrombolytic agents, tissue-type plasminogen activator (t-PA), streptokinase (SK) and a genetically engineered variant of t-PA composed of the second kringle and the protease domain (K2P), cause the dissolution of haemostatic plugs of differing ages was investigated in a novel rabbit model. Standardized incisions were made on the rabbit ear and the wounds were left to heal for 0.5 h or 24 h, before the thrombolytic agents were infused. In the absence of heparin, t-PA showed little discrimination between clots of different ages (36% and 28% lysis of the 0.5 h and 24 h wounds, respectively). In contrast, K2P and SK showed a pronounced fresh clot selectivity since they were significantly more effective in lysing fresh clots than old ones (68% and 4% lysis for K2P and 72% and 36% for SK, respectively). In the presence of heparin the potency of t-PA on fresh clots was considerably increased whilst the effect on old clots was not affected, a fresh clot selectivity for t-PA (64% lysis of fresh clots, 24% lysis of old clots) was thus effected. Heparin did not significantly affect the fresh clot selectivity of K2P or SK, although lysis of old clots was increased (from 4% to 36%) when it was given together with K2P. Furthermore, heparin did not affect the time to onset of bleeding nor was the bleeding time prolonged by its addition. The bleeding time observed for t-PA (20-25 min) was markedly shorter than that found for K2P or SK (40-50 min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Molecular basis of fibrinolysis, as relevant for thrombolytic therapy

The fibrinolytic system comprises an inactive proenzyme, plasminogen, that is converted by plasminogen activators to the active enzyme, plasmin, that degrades fibrin. Two physiological plasminogen activators have been identified: tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). Plasminogen activation for clot lysis is regulated by specific molecular interactions between tissue-type plasminogen activator (t-PA), plasminogen and fibrin, whereby the lysine-binding sites of the plasminogen molecule play a crucial role by mediating its binding to fibrin, and by controlling the inhibition rate of plasmin by alpha 2-antiplasmin. The recognition that thrombosis within the infarct related coronary artery plays a major role in the pathogenesis of acute myocardial infarction and the observation that early administration of thrombolytic agents results in recanalization of occluded coronary arteries, have provided the basis for the development of thrombolytic therapy in acute myocardial infarction. The elucidation of the biochemical mechanism of fibrin-specific plasminogen activation has fueled the hope that specific and efficacious thrombolytic agents might become available. Comparative studies between the non-fibrin-selective streptokinase and fibrin-selective recombinant t-PA (rt-PA) have shown a difference in efficacy for early coronary artery recanalization, whereas the GUSTO trial has established that clinical benefit in patients with acute myocardial infarction is indeed correlated with the rapidity and frequency of sustained recanalization and that effective thrombolysis requires adequate anticoagulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of thrombolytic therapy on pulmonary-capillary blood volume in patients with pulmonary embolism

To compare the effects of heparin thrombolytic agents in pulmonary thromboembolic disease, we randomly assigned 40 patients with pulmonary emboli but without other clinical cardiopulmonary disease either to heparin followed by oral anticoagulants (21 patients) or to urokinse or streptokinase followed by heparin and then by oral anticoagulants (19 patients). The effects on pulmonary-capillary blood volume and diffusing capacity were compared at two weeks and at one year. The pulmonary-capillary blood volume (in milliliters per square meter of body-surface area) was abnormally low (30 +/- 2.4) [+/- S.E.]; normal, 47 +/- 1.5) in the heparin-treated group at two weeks and remained unchanged at one year. In contrast, it was normal (45 +/- 2.5) in the group receiving thrombolytic agents, both at two weeks and at one year (P < 0.001). The pulmonary diffusing capacity was reduced to 69% of the predicted value in the heparin group at two weeks and 72% at one year, whereas it was 85% of the predicted value in the thrombolytic group at two weeks and 93% at one year (P < 0.001). These results indicate that thrombolytic agents allow more complete resolution of thromboemboli than do heparin and anticoagulants and that they improve capillary perfusion and diffusion.     

Comparative effects of staphylokinase and alteplase in rabbit bleeding time models

BACKGROUND: The pathogenesis of bleeding associated with thrombolytic therapy remains largely unknown, although spontaneous bleeding appears to correlate with bleeding time prolongation. Here, the comparative effects on cuticle bleeding times (CBT) and ear puncture bleeding times (EBT) of recombinant staphylokinase (Sak) and alteplase (recombinant tissue-type plasminogen activator, rt-PA) at equivalent doses, alone and in combination with aspirin and heparin, were studied in rabbits. METHODS AND RESULTS: Groups of 4 to 9 rabbits were allocated to one of the 8 following intravenous infusions: saline; aspirin 15 mg/kg and heparin - 100 IU/kg bolus and 10 IU/kg infusion over one hour; 1.5 mg/kg rt-PA; 1.5 mg/kg rt-PA plus aspirin and heparin; 4.5 mg/kg rt-PA; 0.5 mg/kg Sak; 0.5 mg/kg Sak plus aspirin and heparin and 1.5 mg/kg Sak. Bleeding times were determined 30 and 15 min before and 5, 15, 30 and 60 min after the administration over one min of saline, rt-PA or Sak, by simultaneously severing a nail cuticle (CBT) and by puncturing the ear (EBT). Bleeding times were unaffected by saline and by both doses of Sak in monotherapy. Heparin-aspirin and low dose rt-PA significantly lengthened EBT but not CBT. Both CBT and EBT were significantly prolonged (to a mean of > 4 times pretreatment at 5 min) after high-dose rt-PA and after the combined administration of heparin and aspirin with either Sak or tr-PA. rt-PA provoked significantly longer bleeding than Sak in the CBT (p = 0.001; mean estimated difference = 23 min), but not in the EBT. rt-PA but not Sak degraded plasma fibrinogen dose-dependently. CBT correlated inversely with fibrinogen (r= -0.66, p=0.001) but EBT did not. CONCLUSION: At equivalent doses Sak displays a significantly higher fibrin specificity and prolongs bleeding time less than rt-PA, particularly in the nail cuticle bleeding time model in which larger vessels are injured that require fibrinogen for hemostasis.     

The absence of a procoagulant effect after TNK-t-PA: a comparison with streptokinase and rt-PA

A limitation of current fibrinolytic drugs is the procoagulant activity induced by their administration. TNK is a mutant of tissue plasminogen activator (t-PA) with high fibrin specificity, resistance to plasminogen activator inhibitor-1 and slow plasma clearance, which is administered in a single intravenous bolus. In this study we investigated the procoagulant effect of TNK-t-PA compared to streptokinase, rt-PA or no thrombolysis. Twenty-nine patients with acute myocardial infarction, treated within 6 hours of symptom onset with 1.5 MU streptokinase over 1 hour (n = 12), 100 mg rt-PA in 1.5 hours (n = 12) or 30-40 mg TNK-t-PA in 15 s (n = 5), were studied and compared to 7 patients with contraindications to thrombolysis (control group). All patients received a similar i.v. heparin regimen for at least 24 hours. Blood samples were drawn before the start of treatment (time 0) and after 2 hours. Thrombin formation was assessed as plasma concentrations of thrombin-antithrombin complex (TAT). The four patient groups did not differ significantly in age, sex, time to treatment, infarct location, and TAT values at time 0 (mean value +/- standard error of the mean 9 +/- 2 micrograms/l). Mean TAT levels at 2 hours were 26 +/- 6 micrograms/l in streptokinase treated patients (p = 0.005 vs time 0), 21 +/- 4 micrograms/l in rt-PA treated patients (p < 0.05 vs time 0), 5 +/- 0.6 micrograms/l in TNK treated patients, and 4 +/- 0.4 micrograms/l in controls (NS vs time 0 for TNK and controls). In conclusion, our data suggest that, in patients with acute myocardial infarction, bolus TNK-t-PA, unlike streptokinase or rt-PA infusions, is devoid of procoagulant effects, evaluated 2 hours after its administration.     

Incidence and significance of ventricular tachycardia and fibrillation in the absence of hypotension or heart failure in acute myocardial infarction treated with recombinant tissue-type plasminogen activator: results from the Thrombolysis in Myocardial Infarction (TIMI) Phase II trial

OBJECTIVES: The purpose of this study was to determine the incidence of ventricular tachycardia and fibrillation without hypotension or heart failure after treatment with recombinant tissue-type plasminogen activator (rt-PA), anatomic correlates of their development, the effect of immediate intravenous metoprolol on their occurrence and the outcome of patients with these arrhythmias. BACKGROUND: Malignant arrhythmias after thrombolytic therapy have been reported to occur as a result of coronary reperfusion, which is associated with reduced mortality in patients receiving thrombolytic therapy. METHODS: We analyzed data from 2,546 patients in the Thrombolysis in Myocardial Infarction (TIMI) Phase II trial without congestive heart failure or hypotension during the 1st 24 h after study entry. Forty-nine patients (1.9%) developed sustained ventricular tachycardia or ventricular fibrillation within 24 h of study entry (group 1), and 2,497 patients (98.1%) did not (group 2). RESULTS: Baseline characteristics and admission laboratory values were similar in the two groups. In patients undergoing protocol angiography 18 to 48 h after rt-PA, the infarct-related artery was patient in a greater percent of group 2 patients (87% [1,015 of 1,169]) than group 1 patients (68% [15 of 22], p = 0.01), although angiography was performed less frequently in group 1 than in group 2. More group 1 than group 2 patients died within 21 days (20.4%) (1.6%, p < 0.001). For patients surviving to 21 days, there was no difference in mortality between patients in the two groups in the following year. CONCLUSIONS: Ventricular tachycardia and fibrillation are not markers for reperfusion after thrombolytic therapy. These arrhythmias are associated with occlusion, not patency, of the infarct-related artery. Early mortality is increased in patients who develop ventricular tachycardia and fibrillation, even in the absence of congestive heart failure and hypotension.     

Pitfalls in the economic evaluation of thrombolysis in myocardial infarction. The impact of national differences in the cost of thrombolytics and of differences in the efficacy across patient subgroups

BACKGROUND: The economic evaluation of the results of the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Artery (GUSTO) trial found that recombinant tissue plasminogen activator is more cost-effective than streptokinase for the treatment of acute myocardial infarction. AIM: We evaluated the impact on a cost effectiveness analysis, of the differences in the cost of thrombolytics among countries and of differences in efficacy across patient subgroups. METHODS: We considered the crude costs of streptokinase and recombinant tissue plasminogen activator in Germany, Italy, the United Kingdom, and the United States of America, and the 30-day mortality found in the GUSTO trial. We calculated the incremental costs for each life saved when streptokinase is substituted by recombinant tissue plasminogen activator. We also calculated the incremental costs for each life saved for two protocols implying a selective use of streptokinase and recombinant tissue plasminogen activator (age-selective protocol: recombinant tissue plasminogen activator in patients < or = 75 years, streptokinase in older patients; site-selective protocol: recombinant tissue plasminogen activator in anterior acute myocardial infarction, streptokinase in non-anterior acute myocardial infarction). RESULTS: The incremental costs for each life saved when streptokinase is substituted by recombinant tissue plasminogen activator in all GUSTO patients vary greatly among countries: the incremental costs for each life saved are 31%, 45%, and 97% higher in Germany, Italy, and the United States of America compared to the United Kingdom. The use of a site-selective protocol implies a halved cost-effectiveness ratio compared to the use of recombinant tissue plasminogen activator in all cases of acute myocardial infarction. CONCLUSIONS: (1) The cost-efficacy of recombinant tissue plasminogen activator vs streptokinase in acute myocardial infarction varies greatly among countries due to differences in the cost of drugs. (2) A selective use of thrombolytics for some sites of infarction is more cost-effective than the exclusive use of recombinant tissue plasminogen activator.     

Evaluation of drug treatment of myocardial infarction in public hospitals of Andalusia. GAUME (Andalusian Group for performance of Studies on Drug Utilization)

BACKGROUND: The management of patients with acute myocardial infarction (AMI) has changed over the last decade. The aim of this study was to evaluate the pharmacologic treatment of AMI in the clinical practice, with special emphasis in thrombolytic therapy. MATERIAL AND METHODS: Prospective drug utilization survey, collecting data from 26 hospitals belonging to the Andalusian Health Service, Spain, during one month period. Pharmacologic treatment in the first 24 h was obtained. RESULTS: Out of 379 patients recruited, 52.8% received thrombolytic therapy, although another 19% could have obtained some benefit from that therapy. Alteplase was the most frequently used thrombolytic (65.5%). The regimen prescribed was mainly that followed in GUSTO Study (45.8%) or double bolus (43.5%). In a high percentage of patients the thrombolytic selection was not made according to the results of the literature. Women and patients older than 75 years were less likely to receive thrombolytic therapy. There was a high utilization of aspirin (89.7%), nitrates (84.4%) and heparin (83.6%). CONCLUSIONS: Thrombolytic therapy was prescribed in a higher percentage of patients than is reported in other trials. In spite of that, thrombolytics should have been used in more patients. As alteplase does not have a definitive benefit over streptokinase, protocol is needed when selecting a thrombolytic agent.