Heparin in the prevention and treatment of arterial thromboembolism.
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Angina, Unstable↗
Biomedical subjects
M Verstraete
Publications and source records attributed to M Verstraete.
Advances in thrombolytic therapy.
Alteplase and saruplase are more fibrin-specific thrombolytic drugs than anistreplase. These and the thrombolytic drugs of the first generation (streptokinase and urokinase) have shortcomings and limitations. The prolonged intravenous maintenance infusions have been replaced by a bolus injection, accelerated infusions, or the combined intravenous administration of thrombolytic agents. Numerous truncated alteplase or saruplase molecules have been constructed by deletion and domain substitution or hybrids made of the two molecules without gaining in thrombolytic potency. Recombinant staphylokinase and plasminogen activator from bat saliva have some interesting properties and are being investigated. Thrombus-targeted thrombolytic drugs were constructed using monoclonal antibodies against fibrin fragments or against epitopes of activated platelets. Fibrin-specific thrombolytic drugs require the concomitant use of a potent antithrombotic drug to prevent reocclusion. Whether hirudin or synthetic thrombin inhibitors are superior to heparin and whether novel antiplatelet agents, including monoclonal antibodies to platelet receptors and disintegrins, are more effective than aspirin is under clinical investigation. The place of stable analogues of prostacyclin during thrombolytic treatment is still unsettled.
Angiotensin-Converting Enzyme Inhibitors↗
Correlation between level of heparinization and patency of the infarct-related coronary artery after treatment of acute myocardial infarction with alteplase (rt-PA).
BACKGROUND AND OBJECTIVES: The conjunctive use of intravenous heparin may influence the efficacy of alteplase for coronary thrombolysis in patients with acute myocardial infarction. In this study we examined the relation between the level of intravenous anticoagulation with heparin and sustained coronary artery patency in a subgroup of patients of the European Cooperative Study Group (ECSG) trial. METHODS: In the ECSG trial, patients treated with alteplase and aspirin were randomized to concomitant fixed doses of intravenous heparin (a bolus dose of 5,000 U followed by a continuous infusion of 1,000 U/h or placebo). The current study group comprised 149 of 324 ECSG patients allocated to heparin therapy and 132 of 320 ECSG patients allocated to placebo administration who had both an interpretable coronary angiogram obtained within 6 days of treatment and sufficient plasma samples to assess the level of anticoagulation. Activated partial thromboplastin times, fibrinogen and D-dimer levels were determined on plasma samples at baseline and at 45 min and 3, 12, 24 and 36 h after the start of alteplase administration. RESULTS: The coronary artery patency rate was higher in patients allocated to heparin therapy than in those allocated to placebo (80% and 71%, respectively, p = 0.05). Patients allocated to heparin were classified into three subgroups: 48 patients (32%) with all activated partial thromboplastin times at least twice their own baseline value (optimal anticoagulation), 40 patients (27%) with the lowest activated partial thromboplastin time at 3, 12, 24 or 36 h between 130% and 200% of the baseline value (suboptimal anticoagulation) and 61 patients with at least one activated partial thromboplastin time less than 130% of baseline (inadequate anticoagulation). In the heparin group, coronary artery patency correlated with the level of anticoagulation: 90%, 80% and 72%, respectively, in patients with optimal, suboptimal and inadequate anticoagulation (p = 0.02, optimal vs. inadequate anticoagulation). Heparin administration was associated with a smaller reduction in fibrinogen and a smaller increase in D-dimer level during and after alteplase administration. No correlation was found between fibrinogen or D-dimer levels and coronary artery patency. No intracerebral hemorrhage occurred in these patients; however, bleeding was more frequent in the subgroup with optimal anticoagulation (p = 0.05). CONCLUSIONS: Intense anticoagulation with intravenous heparin enhances coronary artery patency after alteplase treatment of acute myocardial infarction.
Adult↗
Effects of intravenous urokinase versus alteplase on total pulmonary resistance in acute massive pulmonary embolism: a European multicenter double-blind trial. The European Cooperative Study Group for Pulmonary Embolism.
Twelve centers participated in a double-blind study in which 63 patients with angiographically documented acute massive pulmonary embolism were randomly assigned to treatment with either urokinase (4,400 U/kg as an intravenous bolus infusion, then 4,400 U/kg per h over 12 h; n = 29) or alteplase (10 mg as an intravenous bolus infusion, then 90 mg over 2 h) followed by heparin (n = 34). The primary objective was to compare the resolution of pulmonary embolism as judged by the change in total pulmonary resistance over the initial 2 h. Further objectives were to evaluate the changes in total pulmonary resistance over the next 10 h and the degree of angiographic resolution at 12 to 18 h. At 2 h, total pulmonary resistance decreased by 18 +/- 22% in the urokinase group and by 36 +/- 17% in the alteplase group (p = 0.0009). Continuous monitoring of pulmonary artery mean pressure, cardiac index and total pulmonary resistance revealed that these variables improved faster in the alteplase group, with consistently significant intergroup differences from 30 min up to 3 to 4 h. After 12 h, the decrease in total pulmonary resistance was 53 +/- 19% in the urokinase group compared with 48 +/- 17% in the alteplase group and the reduction in the angiographic severity score was 30 +/- 25% compared with 24 +/- 18%, respectively, with no significant intergroup differences. Bleeding was equally frequent in the two treatment groups, except that more urokinase-treated patients experienced hematomas at puncture sites.
Double-Blind Method↗
Plasma fibrinopeptide A levels in patients with acute myocardial infarction treated with alteplase. Correlation with concomitant heparin, coronary artery patency, and recurrent ischemia. The European Cooperative Study Group.
BACKGROUND: Fibrin generation during and after therapy with alteplase may depend on the level of concomitant anticoagulation. The hypothesis that fibrinopeptide A (FPA) levels, as markers of ongoing in vivo fibrin formation, correlate with the angiographic and clinical outcome of thrombolysis is tested. METHODS AND RESULTS: Serial plasma FPA levels were determined in 334 patients of the randomized European Cooperative Study Group trial comparing heparin versus placebo plus alteplase and aspirin in patients with acute myocardial infarction. Median FPA levels (with the 10th to 90th percentiles) were 21 ng/ml (2-390 ng/ml) before treatment in placebo-allocated patients (n = 166) and increased to 49 (15-580), 34 (4-320), 27 (2-240), 29 (2-430), and 30 (3-390) ng/ml after 0.75, 3, 12, 24, and 36 hours, respectively. In heparin-allocated patients (n = 168), median baseline FPA values were 18 ng/ml (2-210 ng/ml) and decreased to 6 (1-110), 5 (1-75), 5 (1-60), 7 (1-100), and 10 (1-170) ng/ml at corresponding time points (p less than 0.0001 for the difference at each time point). Adequate anticoagulation, defined as no activated partial thromboplastin time value below twice the pretreatment value at 3, 12, 24, and 36 hours after initiation of treatment, was obtained in 48 patients assigned to heparin. It was associated with normal median FPA levels (less than or equal to 4 ng/ml) at all time points compared with 12 (2-80), 16 (2-240), and 15 (2-240) ng/ml at 12, 24, and 36 hours, respectively, in heparin-assigned but inadequately anticoagulated patients (n = 102, p less than 0.001 for each time point). In the heparin-treated group, median FPA values tended to be lower at all time points in patients with patent vessels than in patients with occluded arteries, but the difference was significant only at 24 hours (p = 0.04). FPA levels did not correlate with clinically apparent recurrent ischemia or with left ventricular thrombosis on two-dimensional echocardiography. CONCLUSIONS: During and after thrombolytic therapy with alteplase, the enhanced fibrin generation is suppressed by sustained concomitant anticoagulation with intravenous heparin. Adequate anticoagulation warrants individual titration of the heparin dose. High plasma FPA levels 24 hours after alteplase therapy are specific but insensitive markers of vessel occlusion in anticoagulated patients. They do not correlate with clinical outcome.
Coronary Vessels↗
Recombinant tissue-type plasminogen activator and immediate angioplasty in acute myocardial infarction. One-year follow-up. The European Cooperative Study Group.
BACKGROUND: The European Cooperative Study Group conducted two randomized trials in patients with suspected myocardial infarction to assess the effect of 100 mg single-chain recombinant tissue-type plasminogen activator (rt-PA, alteplase) on enzymatic infarct size, left ventricular function, morbidity and mortality relative to placebo (alteplase/placebo trial) and to assess the effect of immediate percutaneous transluminal coronary angioplasty (PTCA) in addition to alteplase (alteplase/PTCA trial). One-year follow-up results are reported. METHODS AND RESULTS: In the alteplase/placebo trial, 721 patients with chest pain of less than 5 hours and extensive ST-segment elevation were allocated at random to 100 mg alteplase or placebo (double-blind) over 3 hours. In the alteplase/PTCA trial, 367 similar patients received alteplase and subsequently were allocated at random to immediate coronary angiography and angioplasty of the infarct-related vessel or control. All patients received aspirin and intravenous heparin. In the alteplase/placebo trial, mortality during the first year was reduced by 36% with alteplase (from 9.3% to 5.6%; difference, -3.7%; 95% confidence interval, -7.5% to 0.2%). Revascularization was performed more frequently after alteplase, and more patients in the alteplase group were in New York Heart Association functional class I or II. Reinfarction tended to occur more frequently after alteplase than after placebo. In the alteplase/PTCA trial, reinfarction was less common after immediate PTCA, and revascularization procedures were less frequent. However, this benefit was offset by a high rate of immediate reocclusion and early recurrent ischemia and by higher mortality at 1 year (9.3% versus 5.4%; difference, 3.9%; 95% confidence interval, -1.5% to 9.2%) in the invasive group. In a multivariate analysis of 1,043 hospital survivors, mortality after discharge was related to coronary anatomy, left ventricular function, age, and previous infarction but not to initial treatment allocation. Reinfarction after hospital discharge tended to be more common after alteplase and related to coronary anatomy. CONCLUSIONS: Benefit from treatment with alteplase, heparin, and aspirin is not diminished at 1 year. Routine immediate PTCA does not confer additional benefit. Prognosis after hospital discharge mainly is determined by coronary anatomy and residual left ventricular function and is unrelated to initial treatment assignment.
Angioplasty, Balloon, Coronary↗
Coronary recanalization rate after intravenous bolus of alteplase in acute myocardial infarction.
The demonstration in animals that recombinant tissue-type plasminogen activator produces prolonged thrombolysis after its clearance from the circulation has prompted a few pilot studies of bolus administration in patients. Alteplase (bolus dose of 70 mg) resulted in the highest recanalization rate in our previous pilot study comparing bolus doses of 50, 60 and 70 mg of alteplase in patients with acute myocardial infarction. The aim of the present trial was to assess the efficacy and safety of the same bolus dose in a larger number of patients. A further objective was to study the angiographic reocclusion rate at 12 to 24 hours in patients who had a recanalized infarct-related coronary artery at 90 minutes and were randomized at that time to a bolus dose or an infusion for 3 hours of 30 mg of alteplase. Sixty patients with acute myocardial infarction and angiographically documented total occlusion of the infarct-related coronary artery before thrombolysis were treated within 5 hours of onset of symptoms with an intravenous 70-mg bolus dose of alteplase (or 80 mg if body weight was greater than or equal to 90 kg). Each patient received 5,000 IU of heparin intraarterially and 100 mg of aspirin by mouth before administration of alteplase. Coronary angiography was repeated 60 and 90 minutes after alteplase administration. The recanalization rate of the infarct-related coronary artery was 55% (95% confidence interval, 43 to 66%) at 60 minutes and 48% (95% confidence interval, 37 to 60%) at 90 minutes. Pretreatment levels of lipoprotein (a) were not significantly related to recanalization.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Pentoxifylline in arterial disease of the legs.
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Arterial Occlusive Diseases↗
Reasons for the lack of benefit of immediate angioplasty during recombinant tissue plasminogen activator therapy for acute myocardial infarction: a regional wall motion analysis. European Cooperative Study Group.
Regional ventricular wall motion analysis utilizing three different methods was performed on predischarge left ventriculograms from 291 of 367 patients enrolled in a randomized trial of single chain recombinant tissue-type plasminogen activator (rt-PA), aspirin and heparin with and without immediate angioplasty in patients with acute myocardial infarction. With univariate analysis, no difference in regional wall motion variables between the two treatment groups was observed. However, with individual baseline risk assessment by multivariate linear regression analysis using baseline characteristics known to be related to left ventricular function after thrombolytic therapy or outcome of coronary angioplasty, or both, an excess of high risk patients in the invasive treatment group was detected. To adjust for this unequal distribution of baseline risk, multivariate linear regression analysis was performed. No benefit of immediate coronary angioplasty was observed after adjustment. Reocclusion or reinfarction, or both, occurred more frequently in the invasive than in the noninvasive treatment group (18% versus 13%, respectively). Among patients with a patent infarct-related vessel on angiography between days 10 and 22 and without reinfarction before angiography, there was a trend toward benefit from the invasive strategy, indicating that reocclusion and reinfarction might be responsible for the lack of benefit of the invasive strategy. This implies that immediate coronary angioplasty may be beneficial in selected patients, provided that these complications can be prevented.
Angioplasty, Balloon, Coronary↗
Value of electrocardiographic scoring systems for the assessment of thrombolytic therapy in acute myocardial infarction. The European Cooperative Study Group for Recombinant Tissue Type Plasminogen Activator.
The value of the Selvester and Cardiac Infarction Injury Scores was assessed in a randomized, placebo-controlled study of intravenous recombinant tissue plasminogen activator (rt-PA) in 721 patients with acute myocardial infarction. Electrocardiograms (ECG) obtained at admission, 6 h and 10 to 22 days after the start of therapy were analysed. Patients with prior myocardial infarction or QRS duration greater than or equal to 120 ms were excluded, leaving 322 in the rt-PA group and 333 in the placebo group. Cumulative 72-h release of alpha-hydroxybutyrate dehydrogenase (HBDH) and global ejection fraction derived from angiography and nuclear scintigraphy were used as independent measures of infarct size. Predischarge results demonstrated a net benefit of rt-PA therapy, with the Selvester Score 11% lower (P less than 0.01) and the Cardiac Infarction Injury Score 5.4% lower (P = NS) in the rt-PA than the control group. Total enzyme release was reduced by 19.2% (P less than 0.001) in the rt-PA group. In patients with inferior infarction, neither enzyme release (r = 0.30 to 0.40) nor ejection fraction (r = 0.22 to 0.31) correlated well with the ECG indices of infarct size. In anterior infarction, the correlations were better, especially between the Selvester Score and enzyme release (r = 0.40 to 0.48) as well as ejection fraction (r = -0.48 to -0.67). It is concluded that ECG scoring systems, especially the Selvester Score, although imperfect are useful to assess thrombolytic therapy in clinical trials. However, their value for the management and assessment of thrombolytic therapy in individual patients is still limited.
Electrocardiography↗
Platelet fatty acids and function in two distinct regions of Belgium: relationship to age and dietary habits.
We compared the dietary habits, fatty acid composition of plasma and platelet phospholipids, and platelet function in two groups of healthy Belgian male subjects, known to differ in their mortality rate from coronary heart disease (CHD). In the Walloon subjects, there was a larger intake of saturated and a lower intake of (n-6) polyunsaturated fats, confirmed by the fatty acid composition of plasma and platelet phospholipids. While plasma HDL and total cholesterol were similar in the present samples of the two communities, platelet aggregation to epinephrine was significantly higher in the Walloon subjects. When the two populations were divided into younger (28-54 years) and older (55-73 years) age groups, the older Walloon subjects exhibited platelet hyper-aggregability to most of the agonists, compared to the other three groups. In addition to dietary fats, alcohol and smoking habits, age was an important determinant of platelet phospholipid fatty acids and platelet reactivity. The present results reinforce those of previous studies, indicating that platelet behaviour is significantly affected by the main risk factors for CHD.
Aging↗
Risk factors, interventions and therapeutic agents in the prevention of atherosclerosis-related ischaemic diseases.
Of the major risk factors for atherosclerosis, high factor VII and fibrinogen levels, genetic predisposition, gender and age cannot be influenced. Reduction of high blood pressure reduces the cerebral but not the coronary vascular risk and correction of dyslipidaemia correlates with cardiovascular risk. Other major risk factors (tobacco consumption, obesity, sedentary lifestyle and diabetes) can also be modified. Aspirin in doses of approximately 300 mg/day may be recommended for the primary prevention of myocardial infarction (MI), but only in those patients with a moderate to high risk of cardiovascular disease. Aspirin reduces the risk of fatal and nonfatal MI by about 50% and also decreases the overall mortality rate among patients with unstable angina. A lower dose of aspirin (150 mg/day) also reduces mortality by 23% in the acute phase of MI. In doses of 300 mg/day, aspirin is useful in the secondary prevention of MI and reduces the overall mortality rate by 15%. Various antiplatelet agents, including aspirin (alone or combined with dipyridamole) and ticlopidine, have proved useful in the prevention of thrombosis in aorto-coronary grafts, provided treatment begins at the latest 6 hours after surgery. The usefulness of antiplatelet drugs has been well established in the prevention of immediate reocclusion following coronary angioplasty, but not in the prevention of late reocclusion. Aspirin and ticlopidine are also beneficial in extracorporeal circulation techniques. In patients with a synthetic cardiac valve prosthesis, antivitamin K-anticoagulants are still indispensable lifelong, but their antithrombotic effect can be reinforced by dipyridamole or aspirin. Diuretics probably provide the best primary protection against cerebrovascular accidents, although medium doses of aspirin may be considered in elderly people at high risk of such accidents. Aspirin (alone or combined with dipyridamole) and ticlopidine may be recommended for the secondary prevention of cerebral ischaemic accidents. Aspirin (with or without dipyridamole) and ticlopidine reinforce the treatment of obliterative arterial disease in the lower limbs.
Aspirin↗
Unresolved issues in the thrombolytic treatment of myocardial infarction.
Despite enormous advances made in understanding of the biochemistry of fibrinolytic agents and their extensive clinical use in acute myocardial infarction a number of unresolved issues remain. There is an intriguing divergence of left ventricular response and reduction of mortality in patients with acute myocardial infarction treated with thrombolytic drugs. It is also difficult to explain why patients treated late have a reduced mortality after thrombolytic treatment. Uncertainty prevails on the validity of thrombolysis in patients with a low and very high risk of mortality. Resistance of coronary occlusion to any thrombolytic is another unexplained fact. Alteplase and saruplase are more fibrin-specific thrombolytic drugs than anistreplase. These and the thrombolytic drugs of the first generation (streptokinase and urokinase) have shortcomings and limitations. It is being explored whether prolonged intravenous maintenance infusions are more effective if replaced by a bolus injection, accelerated infusion or the combined intravenous administration of thrombolytic agents.
Age Factors↗
[Psychogenic hemorrhages].
Psychogenic "purpura" consists in the spontaneous appearance of recurrent bruising, it is a reality which is still unexplained. Most often woman with an underlying emotional disorder are affected. In addition to cutaneous ecchymoses and hematomas they may have menometrorrhagia, hematuria, epistaxis and gastrointestinal bleeding in addition to many other complaints encompassing multiple organ systems. Cutaneous bruising is heralded by a burning or stinging sensation followed after a few hours by local warmth, puffiness and erythema, most often with some itching. The pain subsides when the ecchymoses appear a day later or earlier. Blood coagulation and hemostatic tests remain normal in all patients. A rare but poorly studied variety of psychogenic bleeding are religious or other stigmata with periodic bleeding at hands and feet, under the left breast and at the forehead, occasionally with bloody tears. It would be risky to substitute one poorly understood diagnosis (stigmata) with another (hysterical conversion). It is very difficult to distinguish spontaneous psychogenic from selfinflicted iatrogenic bleeding (purpura factitia) because patients may have the same obsessive-compulsive behavior or hysterical trait. Moreover, patients with self-induced bleeding act in a most clever manner and their continuous observation is difficult. The differential diagnosis with the "battered child" syndrome is rather easy. Other bleeding disorders with normal coagulation tests are an inherited failure of the collagen biosynthesis (f.i. Ehlers-Danlos syndrome) or congenital or acquired vascular disorders (purpura senilis of Bateman, vitamin C deficiency, morbus Schamberg, purpura annularis of Majocchi, orthostatic purpura). There is virtually no scientific information on the interaction between the nervous system and hemostasis or blood coagulation. The only therapeutic approach in patients with psychogenic bleeding is psychiatric with particular attention to the sociocultural background of the patient and his family.
Child↗
Usefulness of high-frequency analysis of signal-averaged surface electrocardiograms in acute myocardial infarction before and after coronary thrombolysis for assessing coronary reperfusion.
The incidence of late potentials on the signal-averaged electrocardiogram before and after coronary thrombolysis was studied in 54 patients with an acute myocardial infarction of less than or equal to 5 hours' duration and with an angiographically documented total occlusion of the infarct-related coronary artery on admission. A significant (p = 0.038) 50% relative reduction in the incidence of late potentials was observed in the group of 35 patients who underwent reperfusion: from 16 of 35 (46%) before to 8 of 35 (23%) at 120 minutes after the start of thrombolytic treatment. No significant reduction was seen in the 19 patients in whom thrombolysis was unsuccessful: from 8 of 19 (42%) before to 7 of 19 (37%) afterward. Despite successful recanalization, late potentials persisted or newly developed after thrombolytic therapy in 8 of 54 patients (15%). It is concluded that successful thrombolysis reduces the incidence of late potentials on the signal-averaged electrocardiogram but that the sensitivity and specificity of this finding are not high enough to allow reliable monitoring of coronary reperfusion at the bedside.
Arrhythmias, Cardiac↗
Fast Multiplex polymerase chain reaction on boiled clinical samples for rapid viral diagnosis.
An assessment of optimal conditions for rapid simultaneous amplification of multiple human papillomavirus (HPV) sequences has been made using Thermus aquaticus DNA polymerase. All variables of practical value were studied by amplifying known target-sequences from ten-fold dilutions of well characterized cell lines. In our hands, Fast Multiplex PCR (FM-PCR), the technique of running multiple PCR reactions simultaneously with minimum incubation time at each temperature, was highly sensitive (amplification factor = 5 x 10(9) after 50 cycles), specific (100%) and reproducible (100%) for several microbiological applications. Diagnosis was generally obtained in less than 5 h after sampling. The results show that, after optimization of assay conditions, efficiency and specificity of Multiplex PCR depends exclusively on the primers design and concentration of the primers.
Base Sequence↗
Angiographic assessment of the infarct-related residual coronary stenosis after spontaneous or therapeutic thrombolysis.
The severity of the infarct-related residual coronary stenosis after spontaneous or therapeutic thrombolysis was quantitatively assessed in 91 patients with an acute myocardial infarction who were allocated to treatment in the acute stage with either a thrombolytic agent (100 mg of recombinant tissue-type plasminogen activator given over 3 h, 49 patients) or a placebo (42 patients). Heparin and aspirin were given to both groups until angiography was performed. Digital subtracted images of the infarct-related coronary vessel were obtained 10 to 14 days after hospital admission and were subsequently analyzed with the use of a computer-assisted coronary stenosis measurement system. Neither treatment group differed significantly in age, gender or location of the culprit coronary lesion. Median values (90% range) in the thrombolysis and control groups were, respectively, 1.95 (0.9 to 5.3) mm versus 1.7 (0.9 to 3.4) mm for stenosis length; 1.4 (0.8 to 2.7) mm versus 1.4 (0.9 to 1.8) mm for minimal luminal diameter; 57% (36% to 75%) versus 58% (44% to 71%) for diameter obstruction; 82% (59% to 95%) versus 82% (68% to 92%) for geometric area obstruction; and 78% (58% to 91%) versus 79% (66% to 90%) for densitometric area obstruction. The difference between the two groups was not statistically significant for any of these measurements. Thus, in this study no significant differences in anatomy or severity of residual coronary stenosis could be demonstrated at 10 to 14 days after an acute myocardial infarction in patients with a recanalized infarct-related vessel, whether or not thrombolytic therapy was given on admission. These results indicate that with effective antithrombotic treatment, gradual endogenous fibrinolysis or more rapid lysis induced by the infusion of a thrombolytic agent results in a similar infarct-related coronary lesion at the time of hospital discharge.
Angiography, Digital Subtraction↗