Agents In Acute Myocardial Infarction Research Articles

Thrombolytic fibrin specificity influences activated partial thromboplastin time prolongation in vitro.

Despite limited comparative data, guidelines suggest the same concomitant unfractionated heparin (UFH) dose for all fibrin-specific thrombolytic agents in acute myocardial infarction. Since a supratherapeutic activated partial thromboplastin time (aPTT) correlates with adverse outcomes, clarifying effects of various agents on aPTT are needed. The present in vitro study evaluated the influence of alteplase (rt-PA), reteplase (r-PA), and tenecteplase (TNK) on aPTT prolongation. Blood samples from healthy volunteers (n = 12) were treated with equipotent concentrations of rt-PA, r-PA, and TNK, with and without UFH. Samples of each treatment group were incubated at 37 degrees C; aPTT and fibrinogen activity were measured after 4 h. Mean aPTT values for rt-PA alone and r-PA alone were prolonged versus those of TNK alone (P = 0.001 for both). Combined with UFH, rt-PA and r-PA increased the aPTT versus UFH alone (P < 0.05 for both). Interestingly, TNK + UFH reduced the aPTT versus UFH alone (P < 0.001). A negative correlation existed between fibrinogen activity and aPTT for all treatments, except TNK alone. The present investigation illustrates that an agent with maximal fibrin specificity (TNK) has minimal effect on the aPTT, while agents with less fibrin specificity are more likely to prolong the aPTT, with and without UFH present.

Towards safer thrombolytic therapy

Plasminogen activators (PA) are unique agents that are currently applied as thrombolytic therapy to achieve rapid vascular reperfusion. Regimens of PA plus anticoagulants and antiplatelet drugs have attained a high degree of sophistication and predictable rates of positive clinical outcomes for acute myocardial infarction (MI), ischemic stroke, pulmonary embolism (PE), deep vein thrombosis (DVT), and thrombosed catheters. Included in the repertoire are newly approved mutants of tissue plasminogen activator (TPA), which have biochemical advantages that allow for bolus administration. Yet, despite tremendous effort devoted to enormous trials to establish the clinical efficacy of these agents in acute MI, mortality results are not superior to those with native TPA or streptokinase (SK). Furthermore, all PAs have the potential for hemorrhagic complication, most critically intracranial hemorrhage (ICH), occurring in 0.9% of patients treated with native or mutant TPA. It is possible that a limit of clinical effectiveness has been reached, beyond which more potent PAs do not achieve greater benefit without a serious increase in risk of bleeding. A breakthrough is possible, however, if the risk of ICH could be avoided. One solution is the application of the direct-acting thrombolytic enzyme, plasmin. While intravenous plasmin is not effective when administered systemically, regional infusion to a thrombus induces local thrombolysis. Unlike the PAs, plasmin treatment should not cause hemorrhage from vascular trauma sites, as it is neutralized by antiplasmin in the blood. Animal studies are fully consistent with this approach, which offers potential for achieving a truly regional thrombolytic treatment. Semin Hematol 39:206-216. Copyright 2002, Elsevier Science (USA). All rights reserved.

The general concepts of an equivalence trial, applied to ASSENT-2, a large-scale mortality study comparing two fibrinolytic agents in acute myocardial infarction

The general concepts of an equivalence trial, applied to ASSENT-2, a large-scale mortality study comparing two fibrinolytic agents in acute myocardial infarction

Medical decision making in the choice of a thrombolytic agent for acute myocardial infarction. Quebec Acute Coronary Care Working Group.

Little is known about how physicians make decisions when the evidence is incomplete or controversial. While thrombolysis improves survival following acute myocardial infarction (AMI), conflicting evidence exists as to any specific agent's superiority, particularly if cost-effectiveness is considered. Using a Bayesian hierarchical model, the authors examined the patient, physician, and hospital characteristics that are related to the decision-making process concerning the choice of thrombolytic agent in a prospective registry of 1,165 AMI patients receiving thrombolysis. Tissue plasminogen activator (t-PA) was administered to 432 patients (31.8%) and streptokinase (SK) to the remainder. The presence of an anterior infarction, a previous myocardial infarction, low blood pressure, a cardiologist decision maker, younger age, and receiving treatment within six hours after the start of symptoms were independent predictors of receiving t-PA. The levels of importance that physicians accorded to these patient characteristics differed according to their practicing institutions. Generally, they followed evidence-based medicine and reasonably targeted high-risk patients to receive the more expensive t-PA. However, they also preferentially treated younger patients, where only a small absolute advantage appears to exist.

Combination therapy for acute myocardial infarction: glycoprotein IIb/IIIa inhibitors plus thrombolysis.

Although thrombolytic therapy has been a major advance in the treatment of acute ST-segment elevation myocardial infarction (MI), new thrombolytic agents have been unable to improve early reperfusion. Because aspirin has been shown to be a very effective adjunctive agent in patients with acute MI, it has been hypothesized that the use of platelet glycoprotein (GP) IIb/IIIa receptor inhibitors combined with thrombolytic agents would lead to more effective platelet inhibition and improved angiographic and clinical efficacy. Emerging experimental and clinical data, including the Thrombolysis in Myocardial Infarction (TIMI)-14 trial, suggest that combining GP IIb/IIIa receptor inhibition with reduced-dose thrombolytic therapy improves early infarct-related artery patency without increasing bleeding risk. Thus, given the strong clinical and physiologic rationale, clinical investigation in patients with acute ST-segment elevation MI is currently focused on combining GP IIb/IIIa receptor inhibitors with reduced-dose fibrinolytic agents in acute MI.

Novastan (brand of argatroban): a small-molecule, direct thrombin inhibitor.

Because of the unsatisfactory options available for safe and effective antithrombotic therapy, recent, intense research and development efforts have focused on direct, or site-directed, thrombin inhibitors. Argatroban is a small-molecule, reversible, direct thrombin inhibitor selective for the catalytic site of the thrombin molecule. Argatroban's molecular properties (small molecule; fast, selective, and reversible inhibition of the thrombin catalytic site; and similar in vitro potency for inhibiting both clot-bound and soluble thrombin) offer the potential for significant antithrombotic efficacy with minimal systemic anticoagulant effects. Its clinical pharmacologic properties offer the potential for minimal risk of bleeding, very rapid achievement of therapeutic antithrombotic efficacy, predictable dose response, and rapid restoration of the hemostatic systems to baseline on termination of intravenous infusion. The intravenous agent Novastan (brand of argatroban) is currently approved for clinical use in Japan for the treatment of peripheral arterial occlusive disease. Novastan is in advanced clinical development in North and South America for several indications, including (1) anticoagulant/antithrombotic therapy in heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia, and thrombosis syndrome (HITTS); and (2) adjunctive therapy to thrombolytic agents in acute myocardial infarction. Results from these trials are projected to be available by early 1997.

Trial participation leads to a delay in thrombolysis for acute myocardial infarction

AbstractObjectiveTo determine if there is a significant delay in time to thrombolytic administration for patients participating in clinical trials.MethodsA retrospective audit of all patients given a thrombolytic agent for acute myocardial infarction in the Emergency Department of the Gold Coast Hospital in 1995.ResultsTrial participants (n=17) had a mean door to needle time of 61.9 minutes compared with non trial participants (n=66) whose mean door to needle time was 43.2 minutes. This was found to be statistically significant (p&lt;0.05) and equated to a 43% increase in time to thrombolysis for trial participants.ConclusionParticipation in clinical trials leads to a delay in time to thrombolysis for the individual patient which must be weighed against the potential benefit of research trials to the community.

Increased formation of the isoprostanes IPF2alpha-I and 8-epi-prostaglandin F2alpha in acute coronary angioplasty: evidence for oxidant stress during coronary reperfusion in humans.

The role of oxidant stress in cardiac ischemia/reperfusion injury in humans remains controversial. This is due, in part, to the limitations of available indices of oxidant stress in vivo. Isoprostanes are stable, free radical-catalyzed products of arachidonic acid. We assessed their formation in patients undergoing coronary reperfusion via percutaneous transluminal coronary angioplasty (PTCA). We developed specific, mass spectrometry assays for two structurally distinct F2 isoprostanes, 8-epi-PGF2alpha and IPF2alpha-I. Urine samples for isoprostane determination were collected in patients undergoing coronary arteriography (n=11), elective PTCA (n=15), and angiography after thrombolysis for acute myocardial infarction (MI) (n=10). Urinary levels (pmol/mmol creatinine) of both isoprostanes were markedly increased from baseline in the first 6 hours after PTCA for acute MI (105+/-17.8 versus 230+/-66 for 8-epi-PGF2alpha [P=.009] and 466+/-91 versus 833+/-153 for IPF2alpha-I [P=.001]) and returned toward preprocedural values by 24 hours (122+/-18 for 8-epi-PGF2alpha and 457+/-102 for IPF2alpha-I). There was a slight increase in urinary 8-epi-PGF2alpha levels (64.7+/-9.5 versus 84.9+/-10.6; P=.02) after diagnostic coronary arteriography and elective PTCA (88.7+/-7.5 versus 114.3+/-16.1; P=.01). A striking correlation was observed (r=.68, P<.0001; n=33) between urinary 8-epi-PGF2alpha and IPF2alpha-I levels in patients receiving thrombolytic agents for acute MI. Urinary F2 isoprostane levels are elevated in patients after treatments resulting in reperfusion for acute MI. These findings provide evidence consistent with increased oxidant stress in vivo in this setting. Measurement of urinary isoprostanes may offer a noninvasive approach to the assessment of oxidant stress and the efficacy of antioxidant therapies in these syndromes.

PACE-setting research

In the realm of clinical epidemiology, weak associations and small effects are all too common.1 Since many therapies of interest to clinical investigators, such as new thrombolytic agents for acute myocardial infarction, offer important but small gains for patients, even fairly large trials cannot differentiate between treatments that produce a therapeutic effect and those that do not benefit patients.

Thrombolytic Therapy for Acute Ischemic Stroke: What Cardiac Physicians Need to Know

The current status of thrombolytic therapy for acute ischemic stroke is reviewed in relation to early work and to the use of thrombolytic agents in acute myocardial infarction. The case of a patient treated with recombinant tissue plasminogen activator for acute ischemic stroke is described to illustrate the improvement in outcome that can be achieved with this therapy in selected patients. A number of recommendations are included for cardiologists on the use of plasminogen activator in acute ischemic stroke regarding the timing, dosage, selection, and monitoring of patients.

Calcium antagonists during and after myocardial infarction.

Calcium antagonists, or calcium channel entry blockers, have been advocated as cardioprotective agents in acute myocardial infarction (AMI) on the basis of animal experiments, which show that they will reduce the harmful effects of the calcium overload which follows ischaemia, particularly during reperfusion, and also that they will reduce coronary artery spasm. Unfortunately, these promising actions have not translated into clear mortality data. An overview of the large amount of data from properly randomised controlled clinical trials shows clear differences between the dihydropyridine class of calcium antagonists such as nifedipine, and the non-dihydropyridines verapamil and diltiazem. Most of the data with the former group derive from trials with short-acting formulations of nifedipine (TRENT, HINT, SPRINT-I and -II). Overall, none of these trials showed significant benefit in either AMI or post-MI prophylaxis. There was a trend for harm, with HINT stopped early because of excess reinfarction with nifedipine, compared with metoprolol. In contrast, and when taken together, the DAVIT-I and DAVIT-II studies with verapamil show significant reductions in sudden death, reinfarction and total mortality. The greatest benefit occurred in those patients with relatively good left ventricular function. Similar but less significant trends were seen in studies with diltiazem. It is clear that calcium antagonists, unlike beta-blockers, cannot be treated as a similar class. It seems likely that the adverse effects of nifedipine are related to reflex sympathetic cardiac stimulation as a result of the predominantly vasodilator action of these dihydropyridine compounds. Data on newer dihydropyridines with fewer reflex effects are awaited. In the meantime it seems sensible to use proven agents such as beta-blockers or verapamil. These data on AMI and the months following have recently been paralleled by case control studies in hypertension, which similarly have suggested harm from the use of predominantly short acting formulations of nifedipine compared with beta-blockers and which led to a warning statement by the US National Heart, Lung, and Blood Institute on 1 September 1995.

From the experimental myocardial infarction to the clinical acute myocardial infarction: limitations of thrombolytic therapy

Early administration of thrombolytic agents in acute myocardial infarction lowers mortality and preserves left ventricular function. Currently, only one third of infarct patients receive this treatment, the vast majority being excluded because of restrictive criteria and delayed hospital admission. When correctly administered, thrombolytic therapy achieves reperfusion in 50-85% of occluded vessels. Five to 15% of these initially recanalized vessels eventually reocclude. Possible mechanisms of failure of thrombolytic therapy to induce stable coronary reperfusion include thrombus formation during thrombolysis, platelet activation by thrombolysis, fibrin deposition during thrombolysis, and resistance to thrombolysis. Bleeding complications including intracranial haemorrhage remain a major complication. New therapeutic regimens, new thrombolytic agents and more effective anti-thrombotic drugs, together with intervention strategies that anticipate the time of treatment, promise a significant increase of the overall benefits obtainable with thrombolysis in acute myocardial infarction.

Current issues concerning thrombolytic therapy for acute myocardial infarction

Data are now available from three large-scale randomized trials that directly compare the risks and benefits of thrombolytic agents in acute myocardial infarction. In the interpretation of results from the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) trial and its International Extension, the Third International Study of Infarct Survival (ISIS-3), and the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial, there are areas of both agreement and controversy. It is generally agreed that the agents most commonly used in the United States—tissue-type plasminogen activator (t-PA), streptokinase and anisoylated plasminogen streptokinase activator complex (APSAC)—all reduce mortality when given to patients with acute evolving myocardial infarction. Further, it is clear that thrombolytic therapy given to such patients presenting up to 12 h after onset of symptoms reduces the mortality rate by ∼20%, that aspirin therapy for patients presenting up to 24 h reduces the mortality rate by ∼23% and that the benefits of thrombolytic therapy and aspirin are additive. Finally, and of most importance, the earlier administration as well as the more widespread use of thrombolytic therapy and aspirin would save many more lives. The totality of evidence clearly indicates that streptokinase produces significantly fewer strokes and cerebral hemorrhages than either t-PA or APSAC. Whether or not accelerated t-PA has a small advantage for mortality is less conclusive. At present, any small differences in safety, efficacy and ease of administration of different thrombolytic agents are far outweighed by the large benefits that would accrue from earlier administration and wider utilization of any of these drugs.

Current issues concerning thrombolytic therapy for acute myocardial infarction

Data are now available from three large-scale randomized trials that directly compare the risks and benefits of thrombolytic agents in acute myocardial infarction. In the interpretation of results from the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) trial and its International Extension, the Third International Study of Infarct Survival (ISIS-3), and the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial, there are areas of both agreement and controversy. It is generally agreed that the agents most commonly used in the United States—tissue-type plasminogen activator (t-PA), streptokinase and anisoylated plasminogen streptokinase activator complex (APSAC)—all reduce mortality when given to patients with acute evolving myocardial infarction. Further, it is clear that thrombolytic therapy given to such patients presenting up to 12 h after onset of symptoms reduces the mortality rate by ∼20%, that aspirin therapy for patients presenting up to 24 h reduces the mortality rate by ∼23% and that the benefits of thrombolytic therapy and aspirin are additive. Finally, and of most importance, the earlier administration as well as the more widespread use of thrombolytic therapy and aspirin would save many more lives. The totality of evidence clearly indicates that streptokinase produces significantly fewer strokes and cerebral hemorrhages than either t-PA or APSAC. Whether or not accelerated t-PA has a small advantage for mortality is less conclusive. At present, any small differences in safety, efficacy and ease of administration of different thrombolytic agents are far outweighed by the large benefits that would accrue from earlier administration and wider utilization of any of these drugs.

Thrombolysis and intervention in acute myocardial infarction: an overview.

The use of thrombolytic agents in acute myocardial infarction (AMI) has been extensively studied for the past decade and a half and has become the standard of care for most patients presenting early in the course of AMI. Despite this general acceptance, there remains controversy over the choice of thrombolytic, the use of adjunctive anti-platelet and anti-thrombotic agents, the proper role for PTCA, especially direct PTCA, and the potential role for new interventional devices. The intent of this article is to examine in turn each of these areas, reviewing selected data from relevant trials. In so doing we shall develop an overall concept for reperfusion in AMI to quide our ongoing efforts at resolving our remaining therapeutic challenges.

Early intravenous beta blockade and thrombolytlcs in acute myocardial infarction

This article discusses therapy with β blockade and thrombolytic agents in acute myocardial infarction. In large and well-controlled studies both treatment strategies have been shown to increase survival. Both therapies have also been demonstrated to be safe in acute myocardial infarction. Historically, the 2 different treatment strategies have been tested during different time periods, resulting in few studies with the main objective to study the combined effects of the 2 agents. From the data that are presently available, however, there is a clear suggestion of additive beneficial effect and the 2 treatments given in combination are well tolerated.

Clinical and Angiographic Features of Patients with an Occluded Versus a Patent Infarct Vessel After Intravenous Streptokinase for Acute Myocardial Infarction

Despite early treatment with thrombolytic agents for acute myocardial infarction, a significant portion of patients fail to achieve a patent infarct artery. To study the various factors related to achieving patency in the infarct vessel, 201 patients who received streptokinase within six hours of symptoms were studied. All patients underwent cardiac catheterization during the same hospitalization at 5.40 +/- 3.26 days after admission. Forty-five (22.4%) patients were found to have an occluded infarct artery (group 1) and 156 (77.6%) had a patent infarct vessel (group 2). There was no difference in the time from onset of symptoms to receiving streptokinase between the two groups. The two groups were similar to each other with regard to age, gender, history of myocardial infarction or angina, and major risk factors for coronary disease. Coagulation parameters before and after streptokinase therapy, reflecting the lytic state, were similar in both groups. The left ventricular end diastolic pressure was significantly higher and the left ventricular ejection fraction was significantly lower in group 1 than in group 2. These observations suggest that despite early initiation of thrombolytic therapy in patients with acute myocardial infarction, a significant portion of patients fail to achieve a patent infarct artery. This failure cannot be explained by the observed clinical parameters or the lytic state after streptokinase.

Systolic left ventricular function after reperfusion therapy for acute myocardial infarction. Analysis of determinants of improvement. The TAMI Study Group.

Contrast ventriculograms of 542 patients treated with intravenous thrombolytic agents for acute myocardial infarction were examined to define changes in left ventricular ejection fraction and regional wall motion that occur during the first week after reperfusion therapy for acute myocardial infarction and define clinical, acute angiographic and treatment variables related to improvement in global and regional left ventricular function. Intravenous tissue-type plasminogen activator and/or urokinase was administered to 805 patients during acute myocardial infarction. Mean time from symptom onset to thrombolytic therapy was 3 hours (22 patients received therapy within the first hour). Acute and 7-day catheterization were performed. Paired left ventricular ejection fraction and centerline regional wall motion were available in 542 patients (67%). Stepwise, multivariable analysis of clinical, acute angiographic and treatment variables was used to develop two models: One related to improvement in left ventricular ejection fraction, and the second related to improvement in infarct zone regional function. Left ventricular ejection fraction did not change (51.2 +/- 11.1% for acute versus 51.9 +/- 11.0% for 1 week, p = 0.19). Improvement in infarct zone regional function was modest (14%) at 1 week (-2.54 +/- 1.07 standard deviation per chord for acute versus -2.17 +/- 1.24 at 1 week, p < 0.001). Subgroup analysis demonstrated modest improvement in ejection fraction (1.4 +/- 9.5%) and greater improvement in infarct zone function (19%) in patients with successful sustained reperfusion at 1 week. Depressed left ventricular ejection fraction and infarct zone regional wall motion at the acute study were strongly associated with improvement of these parameters at 1 week. Resolution of chest pain before acute catheterization, infarct-related artery flow at acute catheterization, and depressed regional wall motion in the noninfarct zone were associated with improvement in both ejection fraction and regional infarct zone function at 1 week. Notably, the time from the onset of symptoms to initiation of thrombolytic treatment was not related to subsequent improvement in ventricular function. Dramatic improvement in left ventricular systolic function is not common after thrombolytic therapy for acute myocardial infarction. Improvement in global and regional systolic function is most closely related to acutely depressed ventricular function and successful acute coronary recanalization. Thus, patients with the most myocardium in jeopardy and successful coronary reperfusion demonstrate the greatest improvement in global and infarct zone ventricular function. Overall, the magnitude of this improvement is modest, suggesting that the benefits of coronary reperfusion are not solely related to improvement in systolic left ventricular function.

Antiplatelet Agents in Acute Myocardial Infarction and in the Post-infarction Period

(1993). Antiplatelet Agents in Acute Myocardial Infarction and in the Post-infarction Period. Platelets: Vol. 4, No. sup1, pp. 24-25.

Role of Heparin in Coronary Thrombolysis

Although the benefits of coronary thrombolysis are well established, the optimal therapeutic strategy for ensuring rapid and sustained coronary artery patency remains controversial. The available data suggest that the success of coronary thrombolysis depends not only on the induction of clot lysis, but also on the extent to which procoagulant activity that promotes recurrent thrombosis is inhibited. Procoagulant activity increases almost immediately in patients treated with fibrinolytic agents, and persistent increases in thrombin activity have been associated with recurrent coronary thrombosis. Heparin administered intravenously appears to markedly attenuate the thrombin activity associated with thrombolysis and, in patients treated with tissue plasminogen activator (t-PA), prevents early recurrent coronary thrombosis. The results of clinical trials of coronary thrombolysis indicate that conjunctive treatment of patients with heparin improves survival compared with treatment with fibrinolytic agents alone. Although recent clinical trials in which patients were treated with streptokinase suggested that 12,500 units of heparin administered subcutaneously twice daily decreases mortality, this dosage regimen does not induce therapeutic levels of anticoagulation within the first 24 h in most patients. The failure to achieve early therapeutic anticoagulation may account for the lack of mortality benefit in trials in which patients given t-PA were treated with conjunctive subcutaneous heparin therapy. Thus, the available experimental and clinical data suggest that intravenous heparin should be given to patients treated with fibrinolytic agents for acute myocardial infarction.