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PubMed2004

Thrombolysis and adjunctive therapy in acute myocardial infarction: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.

This chapter about antithrombotic therapy for acute myocardial infarction (MI) is part of the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S-187S). Among the key recommendations in this chapter are the following: For patients with ischemic symptoms characteristic of acute MI of < 12 h in duration, and ST-segment elevation or left bundle-branch block (of unknown duration) on the ECG, we recommend administration of any approved fibrinolytic agent (Grade 1A). We recommend the use of streptokinase, anistreplase, alteplase, reteplase, or tenecteplase over placebo (all Grade 1A). For patients with symptom duration < 6 h, we recommend the administration of alteplase over streptokinase (Grade 1A). For patients with known allergy or sensitivity to streptokinase, we recommend alteplase, reteplase, or tenecteplase (Grade 1A). For patients with acute posterior MI of < 12 h duration, we suggest fibrinolytic therapy (Grade 2C). In patients with any history of intracranial hemorrhage, closed head trauma, or ischemic stroke within past 3 months, we recommend against administration of fibrinolytic therapy (Grade 1C+). For patients with acute ST-segment elevation MI whether or not they receive fibrinolytic therapy, we recommend aspirin, 160 to 325 mg p.o., at initial evaluation by health-care personnel followed by indefinite therapy, 75 to 162 mg/d p.o. (both Grade 1A). In patients allergic to aspirin, we suggest use of clopidogrel as an alternative therapy to aspirin (Grade 2C). For patients receiving streptokinase, we suggest administration of either i.v. unfractionated heparin (UFH) [Grade 2C] or subcutaneous UFH (Grade 2A). For all patients at high risk of systemic or venous thromboembolism (anterior MI, pump failure, previous embolus, atrial fibrillation, or left ventricular thrombus), we recommend administration of IV UFH while receiving streptokinase (Grade 1C+).

Aspirin↗

PubMed2000

Changes in mortality of acute myocardial infarction as a function of a changing treatment during the last two decades.

Forty years ago, after the establishment of coronary care units, a significant decrease in mortality of acute myocardial infarction was noted. Twenty years ago, the break-through of thrombolysis realized once again a significant decrease in mortality. In this study we compare, in a rather small community hospital, the mortality and safety of thrombolytic therapy in acute myocardial infarction with a more conventional, conservative medical therapy. We examined all cases of acute myocardial infarction between 1978 up to 1998 inclusive, concerning treatment and mortality rate after a six month period. To be included in the study, acute myocardial infarction had to fulfill particular inclusion criteria. A total of 1863 cases of acute myocardial infarction were included. The mortality rate of patients with acute myocardial infarction treated with thrombolytic agents was strikingly lower and statistically very significantly different (p < 0.001) in comparison with the mortality rate of patients treated with heparin or coumarine derivatives. The mortality rate dropped from 10.57% in the coumarine group and from 14.95% in the heparin group to 5.41% in the alteplase group, to 4.95% in the anistreplase group and 4.00% in the streptokinase subgroup. The complications directly connected to the treatment did not seem to be different between the five groups, and they were also not more frequent by using thrombolytic agents. In the last 20 years, better preventive measures (life habits, diet, medication) and trials to better control the risk factors have not influenced greatly the average amount of cholesterol in patients with an acute myocardial infarction. Also the percentage of patients with high blood pressure has hardly decreased over the last 20 years. The mortality associated with acute myocardial infarction has decreased significantly with the use of thrombolytics. In most cases, thrombolytics are administered routinely and safely. In this way, they are the first choice therapy for myocardial infarction in smaller hospitals. To obtain excellent coronary patency, thrombolytic agents with a long half-life and with PAI-1 resistance are required in the future. The current measures and medical therapies seem to be insufficient to control the risk factors for coronary atherosclerosis.

Cholesterol↗

PubMed1995

Drug interactions with thrombolytic agents. Current perspectives.

Thrombolytic agents are widely used for the treatment of acute thromboembolic diseases, especially acute myocardial infarction (AMI). These compounds include streptokinase, anistreplase, alteplase, urokinase and, although not commercially available yet, saruplase (prourokinase). The therapeutic window of these compounds is relatively small and subtherapeutic or toxic plasma concentrations may have serious clinical implications (insufficient thrombolysis, reocclusion and bleeding). Among the factors that affect the pharmacokinetics and pharmacodynamics of thrombolytic agents, comedication is especially relevant since these drug interactions are partly predictable and sometimes preventable. Based on knowledge of the pharmacology of thrombolytic agents and general mechanisms by which pharmacokinetic drug interactions occur, interactions with alteplase and saruplase are expected. The clearance of alteplase is dependent on hepatic blood flow (HBF), and scientific evidence is emerging that saruplase is also a high-clearance compound. Each pharmacological agent that alters HBF and is given concurrently with one of these agents can change the plasma concentrations of those thrombolytics. Although there are no published data confirming drug-induced changes in the metabolism of alteplase or saruplase by this mechanism in humans, indirect supportive evidence (clinical observations and animal experiments) is available. An overview is presented of the anticipated effects of compounds that are frequently coadministered with thrombolytic agents on the pharmacokinetics of the thrombolytics with high-clearance properties. Since the clearance of these thrombolytics may be strongly affected by hypoperfusion of the liver as a result of cardiogenic haemodynamic failure, the role of circulatory changes in potential drug-drug interactions is also discussed. Pharmacodynamic drug interactions are highly relevant in the treatment of acute thrombotic lesions and are still being evaluated to further optimise treatment strategies. As most of these treatments exist as combinations of thrombolytic, antithrombin and antiplatelet compounds, beneficial effects are partly offset by bleeding complications. Changes in the pharmacokinetics and/or pharmacodynamics of thrombolytic agents may have serious consequences. It becomes imperative for the practising physician to be aware of benefits and risks of interactions with thrombolytic agents and especially of the fact that the principal way by which the pharmacokinetics of alteplase and, presumably, saruplase can be affected is by drug- and/or haemodynamic failure-induced changes of HBF.

Drug Interactions↗

PubMed1989

Tissue-type plasminogen activator. A review of its pharmacology and therapeutic use as a thrombolytic agent.

Coronary arterial thrombolysis is becoming an established treatment of acute myocardial infarction. If given early enough, it recanalises occluded coronary arteries, salvages myocardial function and reduces mortality. A reduction of mortality in patients with acute myocardial infarction has now been demonstrated for streptokinase, anisoylated plasminogen streptokinase activator complex (APSAC; anistreplase) and recombinant tissue-type plasminogen activator (rt-PA). From the biochemical point of view, rt-PA has several attractive properties. It is similar to or identical with the physiological plasminogen activator in blood, it does not induce an antibody response, and it is more fibrin-specific than most or all other currently known thrombolytic agents. The rate of recanalisation of occluded coronary arteries with rt-PA is about 60 to 80% in non-comparative and placebo-controlled trials. rt-PA was similar in efficacy to urokinase in the only trial to compare the 2 agents. In 2 comparative trials evaluated by meta-analysis, rt-PA appeared more effective than streptokinase for the early recanalisation of occluded arteries. Both agents were comparable in their effects on left ventricular function in 2 comparative trials, but further study is needed to conclusively evaluate this parameter. Moreover, both agents reduce inhospital mortality, but much larger direct comparative trials are required before scientifically valid statements can be made on the relative clinical efficacy of available thrombolytic agents in terms of their effects on both morbidity and mortality. Thus, rt-PA constitutes a notable contribution of recombinant DNA technology to the treatment of thromboembolic disease, the main cause of death and disability in Western societies.

Animals↗

PubMed1989

Use of thrombolytic drugs in non-coronary disorders.

Clinical experience with thrombolytics in non-coronary disorders is limited to the plasminogen activators streptokinase, urokinase and alteplase; therapeutic trials with anistreplase (APSAC) are almost, and with saruplase completely, limited to acute myocardial infarction. In terms of thrombus clearance, thrombolytic drugs are superior to heparin in patients with recent deep vein thrombosis in the pelvis or lower limbs. In aggregate, thrombi younger than 8 days are lysed in approximately 60% of patients treated with streptokinase, urokinase or alteplase. The results of studies assessing the subsequent development of the postphlebitic syndrome are conflicting, but most suggest that thrombolytic therapy can reduce symptoms of chronic venous insufficiency. Currently, the combination of systemic thrombolytic drugs followed by heparin is recommended for patients with acute major pulmonary embolism who are haemodynamically unstable. Streptokinase, urokinase and alteplase have all been shown to accelerate the lysis of pulmonary emboli and to decrease pulmonary vascular obstruction and pulmonary hypertension. Systemic venous or intrapulmonary infusions of alteplase offers the same benefit in terms of angiographic and haemodynamic improvement. A short infusion of 100 mg alteplase over 2 hours seems to be superior to a 24-hour infusion of urokinase. None of the thrombolytic trials in pulmonary embolism have been large enough to demonstrate a reduction in mortality. It is now generally accepted that, unless contraindicated, thrombolytic therapy is the front-line treatment for patients with massive pulmonary embolism and major haemodynamic disturbance. The local treatment of acute arterial occlusion in limb arteries results in rapid clearing of the artery in 67% of patients treated with streptokinase; the corresponding success rates for urokinase and alteplase are 81% and 88 to 94%, respectively. The main question appears to be the identification of patients in whom local thrombolysis is the treatment of choice, as opposed to established therapeutic modalities. Thrombolytic treatment following a major ischaemic stroke is hazardous, although clinical improvement has been noted in a minority of patients with recanalised cerebral arteries. The safety and efficacy of thrombolytic treatment remains unproven for this indication, and its use must be restricted to experimental protocols. Thrombolytic treatment in retinal artery or vein occlusion has, in practice, been abandoned.

Fibrinolytic Agents↗

PubMed1990

Intravenous streptokinase. A reappraisal of its therapeutic use in acute myocardial infarction.

Streptokinase, the first of the thrombolytic agents to be used in acute myocardial infarction, has now been administered to many thousands of patients with this condition. Since early intervention and accessibility of care is paramount in these patients, intravenous infusion of streptokinase has largely replaced intracoronary use. Results of major trials (GISSI, ISIS-2 and ISAM) comparing streptokinase with standard treatment in more than 30,000 patients prove convincingly that intravenous streptokinase increases patient survival after myocardial infarction. The largest trial, ISIS-2, demonstrated a 23% reduction in 5-week vascular mortality after streptokinase use. The greatest benefits occur where streptokinase infusion is initiated early after symptom onset, although late benefit has been observed in patients treated up to 24 hours after pain onset. Importantly, mortality is further decreased by combining streptokinase with aspirin, as shown by a 53% reduction in mortality using the combination in the ISIS-2 trial. Mortality has also been reduced in trials investigating the use of the thrombolytic agents rt-PA and anistreplase. Streptokinase and rt-PA produced similar reductions in mortality in the recent GISSI-2 and International t-PA/Streptokinase Mortality trials, findings which may be further clarified by ongoing comparative trials such as ISIS-3. Reperfusion of about 50 to 60% of occluded coronary arteries occurs with intravenous streptokinase, and left ventricular function is improved. Direct comparisons with rt-PA show a superior effect for the newer agent on early reperfusion, but a similar ability to salvage myocardial function. The complexities of the relationship between reperfusion, left ventricular function and mortality constitute an area of considerable clinical interest requiring further study to clearly differentiate between the drugs available to the physician. The most common adverse events observed during intravenous streptokinase infusion are bleeding complications. An incidence of 3.6% for minor bleeding and 0.4% for major haemorrhage (requiring transfusion) is derived from the combined results of the GISSI and ISIS-2 studies. Bleeding does not appear to be more frequent or severe with intravenous streptokinase than with the more fibrin-selective agent, rt-PA. While the risk to benefit ratio of sequential heparin following streptokinase therapy remains equivocal, the adjuvant use of aspirin confers a clinical advantage over streptokinase alone. In conclusion, streptokinase has now been proven to reduce mortality in patients with acute myocardial infarction, with an acceptable risk of bleeding complications. Given the substantial data that have now accumulated with extensive clinical experience, intravenous streptokinase should be considered a first-line agent in suitable patients.

Fibrinolysis↗

PubMed1992

Thrombolytic therapy for acute myocardial infarction. A review .

In the past 10 years, thrombolytics have become standard therapy for acute myocardial infarction. Although the ability of streptokinase to lyse clot was first recognised in the 1930s, thrombolytic therapy was not used to treat acute myocardial infarction until the early 1980s, when the importance of thrombosis in the pathogenesis of acute infarction was fully recognised. In addition to streptokinase and urokinase, recombinant human tissue plasminogen activator (tPA) and anistreplase were developed and widely used in the 1980s. Saruplase (prourokinase) and BM-06022 (recombinant plasminogen activator) have also undergone human clinical studies. All of these agents are effective at achieving clot lysis and coronary patency. Large, randomised clinical trials have demonstrated that thrombolytic therapy reduces mortality in patients with ST elevation treated within the first 6 to 12 hours of acute infarction, with an approximately 0.5% risk of intracranial haemorrhage. Recent data have more clearly identified which patients benefit from thrombolytic therapy. Efforts have been made to improve the speed of reperfusion, decrease reocclusion, simplify administration and reduce adverse effects. The characteristics of fibrin specificity and more rapid clot lysis with tissue plasminogen activator have not yet been translated into overall clinical benefit compared with the less expensive streptokinase. The lack of close association of improved early patency and improved global left ventricular function with improved survival challenges the very paradigm which led to the use of thrombolytic therapy for acute myocardial infarction. The need for development of additional methods for evaluation of new thrombolytic agents is evident.

Humans↗

PubMed1997

Evaluation of thrombolytic agents.

The mechanism of action of currently available thrombolytic agents, such as streptokinase, urokinase, alteplase (recombinant tissue-type plasminogen activator; rt-PA) and anistreplase (anisoylated plasminogen streptokinase activator complex; APSAC), involves conversion of inactive plasminogen to plasmin, a potent fibrinolytic. However, the relatively weak substrate specificity of first generation agents (streptokinase and urokinase) can result in a state of systemic fibrinolysis and associated bleeding complications. The second generation drugs such as alteplase were developed in an attempt to enhance fibrin specificity, so that only enzymatic conversion of fibrin-complexed plasminogen would take place, thus avoiding systemic fibrinolysis. Results from large clinical trials have failed to consistently show any significant differences between first and second generation thrombolytic agents in the incidence of bleeding. In the clinical setting, thrombolytic agents have been evaluated primarily in patients with acute myocardial infarction and have been shown to significantly reduce morbidity and mortality compared with conservative treatment. The focus of current and future research is to investigate these agents in patients with other vaso-occlusive or ischaemic conditions (e.g. stroke), and also to evaluate different drug administration regimens and the use of adjunctive therapies such as aspirin (acetylsalicylic acid) and heparin.

Drug Evaluation↗

PubMed2000

A review of the long term effects of thrombolytic agents.

Unequivocal evidence exists that reperfusion therapy, when given within 12 hours after onset of symptoms, saves the lives of patients with acute myocardial infarction (MI). As a result, the routine use of such treatment has increased rapidly since the mid-1980s but the rates of utilisation have been relatively static over the last decade at approximately 50% of patients with acute MI. The major question arising in this respect is: is the benefit of reperfusion therapy, which is achieved during the acute phase in evolving MI, maintained on the long term? The main thrombolytic agents currently in use are streptokinase, alteplase, anistreplase, urokinase and reteplase. Other studies compared coronary angioplasty with thrombolytic therapy and investigated the effect of an additional angioplasty procedure after failed thrombolytic therapy. Furthermore, several studies have been performed to investigate the effect of initiation of reperfusion therapy before hospital admission. It is generally agreed that, in particular, patients receiving early treatment within 6 hours from onset of symptoms and patients with ST elevation benefit most from thrombolytic therapy. One would theoretically expect that infarct size reduction achieved by reperfusion therapy would also have a beneficial effect on the survival, not only during the hospital stay but also afterwards, resulting in diverging survival curves between patients who received reperfusion therapy and those who did not. However, the survival curves run perfectly parallel after hospital discharge from 1 year up to year 10 in most studies. The explanation for a lack of extra benefit may be a net result of combining the results of several subgroups. For example, thrombolytic therapy results in more frequent reinfarction especially in the first year, or patients with low left ventricular ejection fraction could survive the hospital phase because of effective thrombolytic therapy, but they survive at high risk. Although several trials suggest that primary percutaneous transluminal coronary angioplasty may be more beneficial than thrombolytic therapy in acute MI, these data should be interpreted cautiously unless confirmed by larger studies with long term results. In addition, evidence exists to suggest that administration of fibrinolytic treatment, under certain conditions, before hospital admission may lead to further improvement of a patient's prognosis. Again, further investigation is warranted. The conclusion is that clear evidence exists that the early improved survival after thrombolytic therapy has been shown to be maintained beyond a decade. However, the expected theorectical additional benefit of reperfusion therapy after hospital discharge has not been observed.

Angioplasty, Balloon, Coronary↗

PubMed1993

Pharmacoeconomic aspects of treatment of acute myocardial infarction with thrombolytic agents.

Thrombolytic therapy reduces early mortality, preserves left ventricular function and improves long term prognosis of acute myocardial infarction. However it is relatively expensive and increasing use will have considerable financial consequences. With competing demand for health resources, information on economic evaluation of this revolutionary therapeutic modality is much needed. Economic evaluation of thrombolytic therapy of acute myocardial infarction entails the assessment of all resources consumed (costs) directly and indirectly in relation to the administration of thrombolytic drugs, versus the beneficial effects (outcome) on health preservation of the patients. To save 1 year of life, the costs of thrombolytic therapy using intravenous streptokinase, alteplase (recombinant tissue plasminogen activator; rt-PA) or anistreplase (anisoylated plasminogen streptokinase activator complex) under standard restricted indication criteria, vary from 1000 pounds British sterling to 1700 pounds British sterling in the UK, SEK3090 to 9660 in Scandinavia and $US35 000 to 800 000 in the US, depending on time delay in starting treatment after pain onset, size of infarct, thrombolytic agents used, study methodology, lists of clinical events considered in cost counting and the discount rate. Cost-utility analyses revealed that the costs of thrombolytic treatment are similar to those of many other treatments for cardiac or other diseases, but methods for evaluating quality of life and utility require further refinement and validation. Economic assessments confirm that thrombolytic treatment of the elderly ( greater than 70 years) is as cost-effective as treatment of younger patients and that both early and late thrombolytic therapy (given 6 to 12 hours after infarction) are beneficial and cost-effective. There are major logistical problems with prehospital thrombolysis, which despite great initial enthusiasm, is unlikely to be cost-effective in saving lives unless savings in time are greater than 1 hour. Cost-effectiveness/utility value of one drug determined from one study cannot be directly compared with that found in other studies using different drugs. More direct prospective comparative trials will be needed in respect of relative benefits and costs with different agents and adjunctive therapies.

Aged↗

PubMed1999

Fibrin-specificity of a plasminogen activator affects the efficiency of fibrinolysis and responsiveness to ultrasound: comparison of nine plasminogen activators in vitro.

In a number of cases, thrombolytic therapy fails to re-open occluded blood vessels, possibly due to the occurrence of thrombi resistant to lysis. We investigated in vitro how the lysis of hardly lysable model thrombi depends on the choice of the plasminogen activator (PA) and is accelerated by ultrasonic irradiation. Lysis of compacted crosslinked human plasma clots was measured after addition of nine different PAs to the surrounding plasma and the effect of 3 MHz ultrasound on the speed of lysis was assessed. Fibrin-specific PAs showed bell-shaped dose-response curves of varying width and height. PAs with improved fibrin-specificity (staphylokinase, the TNK variant of tissue-type PA [tPA], and the PA from the saliva of the Desmodus rotundus bat) induced rapid lysis in concentration ranges (80-, 260-, and 3,500-fold ranges, respectively) much wider than that for tPA (a 35-fold range). However, in terms of speed of lysis, these three PAs exceeded tPA only slightly. Reteplase and single-chain urokinase were comparable to tPA, whereas two-chain urokinase, anistreplase, and streptokinase were inferior to tPA. In the case of fibrin-specific PAs, ultrasonic treatment accelerated lysis about 1.5-fold. For streptokinase no acceleration was observed. The effect of ultrasound correlated with the presence of plasminogen in the outer plasma, suggesting that it was mediated by facilitating the transport of plasminogen to the surface of the clot. In conclusion, PAs with improved fibrin-specificity induce rapid lysis of plasminogen-poor compacted plasma clots in much wider concentration ranges than tPA. This offers a possibility of using single-or double-bolus administration regimens for such PAs. However, it is not likely that administration of these PAs will directly cause a dramatic increase in the rate of re-opening of the occluded arteries since they are only moderately superior to tPA in terms of maximal speed of lysis. Application of high-frequency ultrasound as an adjunct to thrombolytic therapy may increase the treatment efficiency, particularly in conjunction with fibrin-specific PAs.

Combined Modality Therapy↗

PubMed1992

[Thrombolytic agents in myocardial infarction: results of large mortality studies].

Large studies involving several thousand patients have clearly established the effectiveness of thrombolytic therapy in reducing mortality in the acute phase of myocardial infarction: the earlier the treatment, the greater this reduction. The value of late thrombolysis remains to be determined by further studies. This technique can be extended to the oldest subjects who benefit most from this type of treatment, bearing in mind that they are at a greater risk of neurological complications. The effectiveness of thrombolysis is partially dissociated from its effects on left ventricular function. Since the thrombolytic agents (streptokinase, anistreplase and recombinant tissue plasminogen activator) are equally effective in reducing mortality and neurological complications, it seems reasonable to use the cheapest of these drugs as initial treatment, except in some special cases.

Fibrinolytic Agents↗

PubMed1991

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↗

PubMed1990

Properties of a novel plasminogen activator (BM 06.022) produced in Escherichia coli.

Since currently available thrombolytics still show disadvantages, such as administration by infusion, occurrence of intracranial hemorrhage, major hemorrhagic complications, allergic reactions, and high price, a novel tissue plasminogen activator has been developed. BM 06.022 is a t-PA mutant produced in Escherichia coli by DNA technology. It has no oligosaccharide side-chains and comprises the kringle 2- and protease domains of t-PA. Like t-PA, the enzymatic activity of BM 06.022 can be stimulated by fibrin. However, BM 06.022 binds to neither endothelial cells nor fibrin. Despite this, BM 06.022 demonstrates the same fibrin selectivity in vivo as t-PA. Investigation of the pharmacokinetic properties in rats, rabbits, dogs, and primates reveals, depending on species, a 4.5- - 10.4-fold longer dominant half-life and 3- - 8.4-fold slower plasma clearance than t-PA (alteplase). In spite of its lower specific activity in vitro, BM 06.022 has a thrombolytic potency which is 4.6 - 11.5 times higher in vivo than that of alteplase in the rabbit model of venous thrombosis and the canine model of coronary artery thrombosis. BM 06.022 achieves reperfusion significantly more rapid than long-acting anistreplase. Therefore, because of its improved pharmacokinetic properties, BM 06.022 might be administered to infarct patients by i.v. injection in the pre-hospital phase to achieve rapid lysis. Due to its lack of fibrin- and endothelial-cell-binding, combined with retained fibrin selectivity, BM 06.022 further promises to induce fewer hemorrhagic complications than either t-PA or streptokinase.

Animals↗

PubMed1990

The pharmacist's role in thrombolytic therapy.

The pharmacist's role in the administration, appropriate use, and evaluation of thrombolytic agents is discussed. Thrombolytic drugs have been shown to be efficacious when given early in the development of an acute myocardial infarction (AMI). If the drug is to be reconstituted in a central area, there must be immediate response from the pharmacy. If reconstitution is not the pharmacist's responsibility, the pharmacist should still play a role in establishing guidelines for patient selection, drug reconstitution, patient-specific dosing regimens, and concomitant therapy. Pharmacists must also participate in drug-use evaluation. The three thrombolytic agents currently available for the management of AMI are streptokinase, alteplase, and anistreplase. Dosing and reconstitution guidelines for each of these agents are given, and current investigations concerning optimum regimens are summarized. Some of the relative contraindications now used in patient selection need to be examined. It is possible that certain patient subgroups excluded in some trials may benefit from thrombolytic agents. Future clinical trials will provide guidance for the use of thrombolytic agents in these populations. The advent of thrombolytic therapy offers pharmacy an opportunity to expand its role in the drug-use process and to ensure the appropriate use of these agents.

Fibrinolytic Agents↗

PubMed1990

Therapeutic management of acute myocardial infarction.

Criteria for selecting patients for thrombolytic therapy are presented, the major benefits of the currently approved thrombolytic agents are reviewed, and management considerations, including contraindications and the role of ancillary therapy, are discussed. Coronary thrombosis is now believed to play a central role in the pathogenesis of acute myocardial infarction (AMI). Re-establishment of coronary perfusion by thrombolysis has been extensively studied in the past decade and is now regarded as established therapy for patients with ischemic pain of brief (less than six hours') duration who have electrocardiographic ST-segment elevation, are less than 75 years of age, and have no contraindications. Studies supporting thrombolytic therapy have focused on the endpoints of (1) coronary artery patency or reperfusion, (2) improvement in left ventricular function, and (3) reduction in mortality. Benefits for each of these three endpoints have been established and are reviewed with respect to streptokinase, alteplase, and anistreplase, the three agents that have been approved for intravenous use in patients with AMI. The risk of bleeding, including intracranial hemorrhage, remains a concern for all patients. Ancillary therapies to be considered include aspirin, heparin, nitroglycerin, and beta blockers. Recent studies testing different strategies for coronary angiography and angioplasty plus surgery have generally supported a conservative approach, with interventions performed for clinical reasons rather than prophylaxis. Although the currently approved agents have differing pharmacologic profiles, none has yet proved to be clearly superior in the management of patients with AMI. Nonetheless, these agents remain the most promising means of treating selected patients.

Acute Disease↗

PubMed1990

Interventions in acute myocardial infarction.

Results of multiple studies have amply verified the benefit of urgent coronary revascularization for patients who have acute myocardial infarction (MI). Currently, intravenous thrombolytic therapy is the treatment of choice for many patients, especially those 75 years old or younger who present within 6 hours of symptom onset and who are without contraindications to thrombolytic therapy. Some patients treated within 6-24 hours of symptom onset may also benefit, but this remains unproven. The thrombolytic agents currently in use or being extensively evaluated include streptokinase, urokinase, tissue-type plasminogen activator (t-PA), anisoylated plasminogen streptokinase activator complex (APSAC or anistreplase), and single-chain urokinase-type plasminogen activator (scu-PA). The agent t-PA has the potential advantage of being clot selective and, thereby, relatively fibrinogen sparing, and its efficacy in terms of restoration of vessel patency is less dependent on the time of administration as compared with that of streptokinase and urokinase. It is not yet known whether this will translate into improved patient survival as compared with that achieved by the less-expensive agents streptokinase and APSAC. Treatment regimens of combination thrombolytic agents have been developed, but the optimal combinations have not yet been determined. Patients who are in cardiogenic shock and those in whom thrombolytic therapy is contraindicated can probably benefit from angioplasty or bypass surgery. Results of several studies have suggested that immediate angioplasty after successful thrombolysis is not beneficial; however, the potential benefit of angioplasty or bypass surgery for failed thrombolytic therapy is yet to be evaluated. Although many advances have been made, further research is clearly needed in the area of reperfusion.

Angioplasty, Balloon, Coronary↗

PubMed1994

[Prehospital thrombolytic therapy of acute myocardial infarct].

The extent of myocardial damage occurring during acute myocardial infarction is time dependent, and there is abundant evidence from most clinical trials that mortality reduction is greatest in patients treated early with thrombolytic agents, although beneficial effects have been shown with treatment initiated up to 12 hours after onset of symptoms. This temporal dependence of benefit was most clearly seen with the 47% mortality reduction obtained with streptokinase given within the first hour in the GISSI-1 trial (Table 1). The process of infarction may be completely aborted if reperfusion is initiated within 30 minutes after symptom onset. Current approaches designed to reduce the time delay between onset of symptoms and the initiation of thrombolytic treatment include increasing public awareness of the need to seek prompt medical attention in the event of chest pain, reducing in-hospital delays in initiation of thrombolytic therapy, and administration of thrombolytic agents in the prehospital setting. Since the first paper on prehospital thrombolysis by Koren et al. in 1985 there have been numerous studies published, including several randomized trials comparing prehospital and in-hospital initiation of thrombolytic therapy (Table 2). In randomized studies patients received in the pre-hospital phase either a bolus or infusion with the thrombolytic agent followed by placebo after hospital admission, or placebo when first seen outside the hospital, followed by the thrombolytic agent after arrival at the hospital. This was performed in a double-blind fashion in some of the trials. Some of the studies on prehospital thrombolysis have focused only on feasibility and safety, others on time gain, differences in ejection fraction and mortality benefit. Almost all have conclusively shown the practicability and safety of patient selection and administration of the thrombolytic agent. This positive result was observed in different organizational types of the emergency system: In the Myocardial Infarction Triage and Intervention trial (MITI) patients with chest pain were screened by paramedics using a checklist of clinical inclusion and exclusion criteria. The paramedics then obtained a computer-interpreted ECG which was transmitted to the emergency department in the hospital where a physician made the decision on the form of treatment. The thrombolytic agent was then administered by the paramedic. In the European Myocardial Infarction Project (EMIP) an emergency physician was personally present and responsible in the prehospital setting, whereas in the Grampian Region Early Anistreplase Trial (GREAT) general practitioners made the decision for enrolling the patient.

Double-Blind Method↗