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.     

Thrombolysis

The most widely studied thrombolytic drugs in stroke have been streptokinase (SK) and alteplase. The three large trials with streptokinase were terminated prematurely. The combined results reveal an early increased risk of cerebral haemorrhage and death, with no net benefit at final follow-up, even in subgroups. Some controversy persists, however. The dose may have been inappropriately high, very early treatment has not been fully tested, and concomitant use of aspirin or heparin may have contributed to the deleterious effect. Even so, there is no evidence to guide the choice of a lower dose, streptokinase predisposes to a prolonged anticoagulant effect, and is associated with hypotension which may offset any benefit. The four large alteplase trials in acute stroke were more encouraging. The NINDS study was clearly positive and supporting evidence comes from the two ECASS trials when subjected to meta-analysis. The trials have shown additional functional recovery in 0.6% of patients receiving SK within 6 h and in 7.6% with alteplase, at the expense of excess mortality of 1.1% for alteplase and 11.7% for SK. There was an absolute cerebral haemorrhage excess of 10.7% with SK and 8% for alteplase. If alteplase use is restricted to < 3 h from stroke onset, the NNT is 10.7 with no excess mortality; later treatment (3-6 h) gives an NNT of 26 and absolute mortality of 3.4%. Finally, early fibrinogen depletion with ancrod also appears to have beneficial effects when treatment is started within 3 h of stroke onset. Further trials are still required to establish, inter alia, the outer limit of the therapeutic window, to identify sub-groups of patients in whom clear benefit (or harm) exists and to establish appropriate management protocols for concomitant treatment. Thrombolysis with alteplase within 3 h of stroke onset may be considered for patients in whom haemorrhage and established infarction have been excluded. Trained assessment is essential, since there is an increased risk of haemorrhagic conversion that may be fatal. Patients considering thrombolytic treatment should appreciate that 1 in 10 patients have improved outcome, 1 in 20 suffer haemorrhagic conversion and 1 in 100 may die as a result of treatment. Treatment much later than 3 h from stroke onset in unselected patients is as likely to kill as to cure.     

Clinical potential of intra-arterial thrombolytic therapy in patients with acute ischaemic stroke

Acute ischaemic stroke is a leading cause of mortality and morbidity around the world. An arterial occlusive lesion is found in the majority of patients with acute ischaemic stroke, and recanalisation has been shown to result in a better clinical outcome. The only widely approved recanalisation strategy is the use of intravenous alteplase (recombinant tissue-type plasminogen activator; tPA) within 3 hours of stroke onset. However, this therapy has limitations, and alternative or supplemental recanalisation strategies need to be considered in a large number of patients with acute ischaemic stroke. One such promising strategy is intra-arterial thrombolysis. This article reviews the pharmacology of the various drugs used for intra-arterial thrombolysis in the setting of acute ischaemic stroke and the results of the clinical trials that have studied their benefit. Three generations of thrombolytic agents have been available for clinical use so far. The first-generation agents such as streptokinase and urokinase were the first to be studied in acute stroke, and a number of positive case reports and series of their intra-arterial use have been reported from around the world. Second-generation products include alteplase and pro-urokinase. The clinical benefits of intra-arterial pro-urokinase were recently proven in a randomised, placebo-controlled study. Third-generation agents, such as reteplase, lanoteplase and tenecteplase, offer superior recanalisation rates with limited systemic adverse effects and might prove to be the agents of choice for intra-arterial acute stroke thrombolysis in the future. The exact administration regimens as well as the identification of patient sub-populations most likely to benefit from intra-arterial thrombolysis are subjects of current investigations, and hopefully firmer guidelines will be established in the next few years, once the results of the clinical trials are available.     

Intravenous thrombolysis in acute ischaemic stroke: optimising its use in routine clinical practice

Stroke is a common and important medical problem. Intravenous thrombolysis with alteplase (recombinant tissue plasminogen activator; rtPA) is the only available direct treatment that reduces neurological injury following ischaemic stroke. Strong efficacy data from randomised, controlled trials support the use of intravenous thrombolysis to improve outcomes for patients with acute ischaemic stroke. Numerous studies have provided effectiveness data that demonstrate that intravenous thrombolytic therapy can be given safely outside clinical trial settings. However, effectiveness studies have demonstrated that intravenous thrombolytic therapy is often given despite protocol violations when it is prescribed in routine clinical practice. Protocol violations must be avoided because they are associated with adverse events including higher mortality and increased haemorrhagic complications. Although thrombolytic therapy with alteplase is currently being used in only <10% of patients with acute ischaemic stroke, recent studies demonstrate that quality management efforts can improve both the absolute rate of use as well as the proficiency with which alteplase is administered. Given the complexities inherent in prescribing thrombolysis for patients with acute ischaemic stroke, alteplase should be used by clinicians who are experienced in the diagnosis and management of stroke, working in medical centres that have systems in place to ensure that alteplase is given without protocol violations.     

Safety and efficacy of tenecteplase in acute myocardial infarction

The use of intravenous thrombolytic agents has revolutionised the treatment of acute myocardial infarction. However, the improved mortality achieved with these drugs is tempered by the risk of serious bleeding complications, especially intracranial haemorrhage (ICH). Tenecteplase (TNKase?, Genetech Inc.) is an engineered variant of alteplase (Activase^®, Genentech Inc.) designed to have increased fibrin specificity, greater efficacy and a longer half-life. The longer half-life of tenecteplase compared to alteplase allows for convenient single bolus administration of the drug. In addition, tenecteplase dosing is based on actual or estimated patient weight, which enhances both the safety and efficacy outcomes. Large clinical trials have demonstrated equivalence in mortality and ICH between tenecteplase and alteplase. Compared to alteplase, tenecteplase use leads to lower rates of bleeding complications and a decreased risk of ICH among low weight, elderly women.     

Thrombolytic therapy for acute ischaemic stroke: what can we do to improve outcomes?

Constant efforts are being made in the stroke community to aim for maximum benefit from thrombolytic therapy since the approval of intravenous recombinant tissue plasminogen activator (rt-PA; alteplase) for the management of acute ischaemic stroke. However, fear of symptomatic haemorrhage secondary to thrombolytic therapy has been a major concern for treating physicians. Certain imaging and clinical variables may help guide the clinician towards better treatment decision making. Aggressive management of some predictive variables that have been shown to be surrogate outcome measures has been related to better clinical outcomes. Achieving faster, safer and complete recanalization with evolving endovascular techniques is routinely practiced to achieve better clinical outcomes. Selection of an 'ideal candidate' for thrombolysis can maximize functional outcomes in these patients. Although speed and safety are the key factors in acute management of stroke patients, there must also be a systematic and organized pattern to assist the stroke physician in making decisions to select the 'ideal candidate' for treatment to maximize results.     

Benefit-risk assessment of treatments for heparin-induced thrombocytopenia.

Patients with heparin-induced thrombocytopenia (HIT) are at high risk of thrombosis and should be treated with alternative anticoagulant therapy to reduce complications. The current treatment of choice is one of the approved direct thrombin inhibitors, argatroban or lepirudin. These drugs have been proven to be safe and effective in multicentre clinical trials where dosage regimens have been established for prophylaxis and treatment of thrombosis. Argatroban has also been tested and approved for use in invasive cardiology procedures in the HIT patient. Dosage regimens for other clinical uses, such as cardiac surgery, have not yet been established for either drug. The safety and effectiveness of the thrombin inhibitors is dependent on their use according to established guidelines. Other treatment options that may be effective for the patient with HIT include dextran, plasmapheresis, intravenous gammaglobulin and aspirin (acetylsalicylic acid). Although used historically, these options have not been tested in rigorous clinical trials. For life- and limb-threatening thrombosis, thrombolytic agents and/or surgery may provide benefit. Because the risk of bleeding is high from these procedures, they should be performed only by an experienced practitioner. Several studies have shown that patients with HIT requiring continued anticoagulation are best managed with a warfarin derivative initiated while under full anticoagulation with a thrombin inhibitor. There is a risk of skin necrosis and bleeding if guidelines for dose administration and monitoring of warfarin are not followed. Subsequent use of heparin or a low molecular weight heparin after resolution of the clinical episode of HIT can be hazardous, particularly within the first 3 months. If laboratory testing is negative, heparin may be cautiously reinstituted for short-term use (1-2 hours) with monitoring for platelet count decrease and thromboembolism. The pregnant patient with HIT requiring anticoagulation represents a particular challenge, where there is no drug of choice at present. Although today there are realistic treatment options for the patient with HIT, the morbidity and mortality associated with this disease have not been eliminated. Awareness and early treatment of HIT remain important components of the clinical care for patients exposed to heparins. Future therapeutic developments based on a better understanding of the pathophysiology of HIT may further improve clinical outcomes. Despite some limitations, the current treatment options for patients with HIT provide unparalleled benefit compared with the treatment options available only a few years ago.     

Novel thrombolytic drugs: will they make a difference in the treatment of ischaemic stroke?

Treatment of acute ischaemic stroke aims to recanalize the occluded artery, salvage the at-risk brain tissue and thus minimize neurological sequelae. Efforts a decade ago have led to the only currently approved medical treatment for acute ischaemic stroke, i.e. intravenous alteplase given within 3 hours of stroke onset. Recanalization occurs in only one-half of the patients receiving alteplase, and only approximately 5% of all ischaemic stroke patients in industrialized countries receive this treatment. Studies are currently being carried out to determine whether intravenous alteplase would be safe and effective for up to 4.5 hours after ischaemic stroke onset, and whether it should be followed by an intra-arterial approach. Two novel thrombolytic drugs being studied for acute ischaemic stroke are desmoteplase and tenecteplase. Although the first trials were promising, the most recent evidence suggests that desmoteplase is not superior to placebo, even in carefully selected patients, in the 3- to 9-hour time window after stroke onset. Tenecteplase has only been studied for acute ischaemic stroke in a single noncontrolled, dose-finding trial in the 3-hour time window after stroke onset, which suggested a similar efficacy to that demonstrated in the historical data from the alteplase trials. A trial to compare the safety and efficacy of tenecteplase versus alteplase is ongoing. Safer and more effective thrombolytic drugs for the treatment of ischaemic stroke are thus being sought. Such agents will be welcome, but they are not here yet. While waiting we are likely to see the emergence of additive therapies, including ultrasound insonation, neuroprotective/regenerative agents and invasive intra-arterial techniques. Novel thrombolytic drugs, or other novel therapies, possess great potential to make a difference in the future, but the most urgent priority now is in the organization of stroke treatment in such a way that more patients receive the currently available optimal treatments.     

Management of acute ischaemic stroke in the elderly: tolerability of thrombolytics

Stroke and its consequences are of global concern. Although stroke can affect individuals of any age, it primarily affects the elderly. It is among the leading causes of severe disability and mortality. In recent years, acute stroke has become a medical emergency requiring urgent evaluation and treatment. Effective management of patients with acute stroke starts with organisation of the entire stroke care chain, from the community and prehospital scene, through the emergency department, to a dedicated stroke unit and then to comprehensive rehabilitation. Intravenous thrombolysis with alteplase (recombinant tissue plasminogen activator; rt-PA) 0.9 mg/kg (maximum dose 90 mg) was shown to significantly improve outcome of acute ischaemic stroke, despite an increased rate of symptomatic intracerebral haemorrhage, if treatment is initiated within 3 hours after the onset of symptoms to patients who meet strict eligibility criteria. Post-marketing studies have demonstrated that intravenous alteplase can be administered appropriately in a wide variety of hospital settings. However, strict adherence to the published protocol is mandatory, as failure to comply may be associated with an increased risk of symptomatic intracerebral haemorrhage. Intra-arterial revascularisation may provide more complete restitution of flow than intravenous thrombolytic therapy and improve the clinical outcome if it can be undertaken in patients with occlusion of the middle cerebral artery, and possibly the basilar artery, within the first hours from stroke onset. However, further data are needed. Although intravenous alteplase is recommended for any age beyond 18 years, elderly patients, in particular patients aged > or = 80 years, were often excluded or under-represented in randomised clinical trials of thrombolysis, so that available data on risk/benefit ratio for the very elderly are limited. Small post-marketing series suggest that despite elderly patients over 80 years having greater pre-stroke disability, the use of intravenous alteplase in this patient group does not significantly differ in effectiveness and complications compared with the same treatment in patients aged under age 80 years. Further studies are necessary and elderly patients with acute stroke should be included in future trials of the merits of thrombolytic therapy.     

Safety and efficacy of tenecteplase in acute myocardial infarction

The use of intravenous thrombolytic agents has revolutionised the treatment of acute myocardial infarction. However, the improved mortality achieved with these drugs is tempered by the risk of serious bleeding complications, especially intracranial haemorrhage (ICH). Tenecteplase (TNKase, Genetech Inc.) is an engineered variant of alteplase (Activase, Genentech Inc.) designed to have increased fibrin specificity, greater efficacy and a longer half-life. The longer half-life of tenecteplase compared to alteplase allows for convenient single bolus administration of the drug. In addition, tenecteplase dosing is based on actual or estimated patient weight, which enhances both the safety and efficacy outcomes. Large clinical trials have demonstrated equivalence in mortality and ICH between tenecteplase and alteplase. Compared to alteplase, tenecteplase use leads to lower rates of bleeding complications and a decreased risk of ICH among low weight, elderly women.     

A nationwide survey of prescribing patterns for thrombolytic drugs in acute myocardial infarction

In November 1988, 164 hospitals enrolled in the Drug Surveillance Network participated in a nationwide survey of prescribing patterns for thrombolytic drugs for patients with an acute myocardial infarction. The results indicated that alteplase has made dramatic inroads, being used exclusively in 14.6% of the hospitals; in 64% of the hospitals both alteplase and streptokinase were on the formulary. Overall, however, only 17% of patients admitted with an acute myocardial infarction were treated with a thrombolytic, and use of these agents varied markedly across institutions. One of the reasons for this low figure may be the current maximum allowable time from onset of symptoms to administration of a thrombolytic. This time limit was less than 6 hours in the majority of hospitals in spite of recent evidence suggesting that these drugs may be effective up to 24 hours after onset of symptoms. The low and variable use of the agents for acute myocardial infarction suggests the need to identify patient- and physician-related obstacles so that overall attitudes and professional practice can be modified to reverse this trend. Given large number of institutions reporting the presence of formal, prospective, pharmacy-initiated monitoring programs, we suggest that clinical pharmacists will play a major role in implementing the necessary changes.     

Drug Treatment of Acute Ischemic Stroke

Acute ischemic stroke (AIS) is the fourth leading cause of death and the leading cause of adult disability in the USA. AIS most commonly occurs when a blood vessel is obstructed leading to irreversible brain injury and subsequent focal neurologic deficits. Drug treatment of AIS involves intravenous thrombolysis with alteplase (recombinant tissue plasminogen activator [rtPA]). Intravenous alteplase promotes thrombolysis by hydrolyzing plasminogen to form the proteolytic enzyme plasmin. Plasmin targets the blood clot with limited systemic thrombolytic effects. Alteplase must be administered within a short time window to appropriate patients to optimize its therapeutic efficacy. Recent trials have shown this time window may be extended from 3 to 4.5 hours in select patients. Other acute supportive interventions for AIS include maintaining normoglycemia, euthermia and treating severe hypertension. Urgent anticoagulation for AIS has generally not shown benefits that exceed the hemorrhage risks in the acute setting. Urgent antiplatelet use for AIS has limited benefits and should only promptly be initiated if alteplase was not administered, or after 24 hours if alteplase was administered. The majority of AIS patients do not receive thrombolytic therapy due to late arrival to emergency departments and currently there is a paucity of acute interventions for them. Ongoing clinical trials may lead to further medical breakthroughs to limit the damage inflicted by this devastating disease.     

Reteplase (r-PA): a new plasminogen activator

Reteplase (r-PA) is a genetically engineered deletion mutant of wild-type tissue-type plasminogen activator. The structural differences lead to different functional properties, such as a prolonged half-life. The compound demonstrated good thrombolytic efficacy in in vitro as well as in animal studies. In angiographically controlled patency studies (GRECO, GRECO-2 RAPID-1, RAPID-2), the double-bolus application scheme was established, and a superior patency profile for reteplase in comparison to alteplase was demonstrated. Mortality studies established reteplase as a safe drug with a 30-day mortality at least equivalent to streptokinase (INJECT) and very similar to alteplase (GUSTO-3). A possible advantage may be the double-bolus application without a need for weight adjustment, especially in a prehospital setting. Thus, reteplase can be regarded as an excellent alternative to streptokinase or alteplase for thrombolytic therapy in acute myocardial infarction.     

Alteplase: descendancy in myocardial infarction,ascendancy in stroke

Tissue type plasminogen activator is available, through recombinant technology, for thrombolytic use as alteplase. Alteplase is relatively clot specific and should cause less bleeding side effects than the non-specific agents such as streptokinase. Alteplase has been used successfully in evolving myocardial infarction (MI) to reopen occluded coronary arteries. It is probably equally effective or superior to streptokinase in opening arteries and reducing mortality in MI. Alteplase is most effective when given early in MI and is probably ineffective when given 12 h after the onset of symptoms. The effectiveness of alteplase in MI can be increased by front loading with a bolus of 15 mg, followed by an infusion of 50 mg over 30 min and 35 mg over 60 min. Percutaneous transluminal coronary angioplasty or stenting is associated with a greater patency and lower rates of serious bleeding, recurrent ischaemia and death than alteplase in MI and is likely to take over from alteplase as the standard MI treatment. A reduced dose of alteplase to increase coronary artery patency prior to angioplasty may be useful in MI. An exciting new indication for the use of alteplase is in stroke, where it has become the first beneficial intervention. Alteplase is used to reopen occluded cerebral vessels but is associated with an increased risk of intracerebral haemorrhage. Alteplase is beneficial if given within 3 h of the onset of stroke but not after this time period. Therefore, the next challenge is to increase the percentage of people being diagnosed and treated within this period. Clinical trials have not established a role for alteplase in the treatment of acute coronary syndromes or deep vein thrombosis. However, alteplase is useful in treating pulmonary thromboembolism and peripheral vascular disease.     

Alteplase: a pharmacoeconomic evaluation of its use in the management of myocardial infarction

Alteplase (recombinant tissue plasminogen activator; rt-PA) is a thrombolytic agent that when given in an accelerated regimen with intravenous heparin has survival advantages compared with streptokinase in the treatment of acute myocardial infarction, as shown by the results of the Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial. Although alteplase is more fibrin-specific than streptokinase, alteplase therapy is associated with a small relative increase in the incidence of haemorrhagic stroke, but appears to cause a small relative decrease in the incidence of major bleeding. Because alteplase has a higher acquisition cost than alternative thrombolytic agents, analyses have been undertaken to assess whether administration of alteplase after myocardial infarction is a cost-effective use of healthcare resources. In retrospective analyses undertaken before completion of the GUSTO trial, it was generally assumed, on the basis of better 90-minute patency rates, that alteplase would provide survival advantages compared with streptokinase or conventional nonthrombolytic therapy. Alteplase had acceptable cost-effectiveness ratios compared with conventional therapy and streptokinase therapy from both third-party payer and hospital perspectives. Subgroup analyses demonstrated that alteplase was more cost effective when given early after symptom onset and when given to patients with large infarcts. Prospective evaluations of the cost effectiveness of alteplase in 3-hour and accelerated regimens have similarly demonstrated that alteplase therapy after myocardial infarction improves survival at an 'acceptable' cost. The largest prospective evaluation undertaken to date was performed in conjunction with the GUSTO trial. Primary analysis, on the basis of the clinical findings of the GUSTO trial and prospective collection of cost data from US patients, revealed that the cost-effectiveness ratio for accelerated alteplase therapy compared with streptokinase was $US32,687 (1993 dollars) per year of life saved (YLS). This value is most relevant for US patients and lies within the definition of 'cost effective' if $US50,000/YLS is the benchmark for acceptable use of resources. The cost-effectiveness ratio for alteplase was most sensitive to assumptions regarding long term survival and cost differences after the first year following treatment. In subgroup analyses, alteplase was a cost-effective treatment option for all elderly patients (> 60 years of age) and all patients > 40 years of age with anterior infarction. Alteplase therapy appears to have in-hospital costs/charges similar to those for primary percutaneous transluminal coronary angioplasty (PTCA), mainly because PTCA appears to have a favourable effect on duration of hospitalisation. Given the technical expertise and facilities required for PTCA, it is likely that thrombolytic therapy will remain the management option of choice in most centres. In conclusion, under the conditions of the GUSTO study, accelerated alteplase in combination with intravenous heparin confers survival advantages compared with streptokinase therapy. While decision-makers must choose how best to use their available healthcare resources, pharmacoeconomic evaluations have confirmed that, on the basis of accepted benchmark values, alteplase therapy is a cost-effective therapeutic option for the treatment of acute myocardial infarction, especially in elderly patients with either anterior or inferior infarcts and nearly all patients with anterior myocardial infarction. Thus, on the basis of clinical and economic data, predominantly provided by the GUSTO trial, alteplase is a cost-effective first-line management option for acute myocardial infarction.     

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.     

Advances in ischemic stroke treatment: neuroprotective and combination therapies

Thrombolysis with intravenous alteplase (recombinant tissue-type plasminogen activator) continues to be the sole recourse for acute ischemic stroke therapy, provided that patients seek treatment preferably within 3 h of stroke onset. The narrow window of efficacy, coupled with the significant risk of hemorrhage and the high mortality rate, preclude the use of alteplase beyond this time frame. Moreover, in part because of safety concerns, only a small percentage (6 – 15%) of eligible patients is treated with alteplase. Clearly, safer and more effective treatments that focus on improving the shortcomings of the present thrombolysis for stroke need to be identified. Therefore, newer thrombolytics are being developed with the goal of minimizing side effects, while also shortening the time of cerebral reperfusion and extending the therapeutic window of efficacy. Besides thrombolytics, new and potentially useful drugs and devices are also being studied either as monotherapeutic agents or for use in conjunction with alteplase. In animal models of stroke, neuroprotective agents that affect various components of the ischemic injury cascade that results in neurodegeneration have shown promise for the latter. Examples of such agents include spin traps that block oxidative stress, metalloprotease inhibitors that prevent vascular damage, anti-inflammatory drugs that suppress inflammation and transcranial infrared laser irradiation, which promotes recovery of function. Ideally, a successful combination of neuroprotectant (drug or device) and thrombolytic therapy for stroke would minimize the side effects of thrombolysis followed by supplementary neuroprotection thereafter.     

Pharmacological revascularization of acute ischaemic stroke: focus on challenges and novel strategies

The only currently approved treatment for acute ischaemic stroke (AIS) is alteplase, a thrombolytic agent given intravenously (IV) within 4.5 hours of symptom onset, in an attempt to reopen occluded intracerebral arteries. However, no more than 5% of all AIS patients receive IV alteplase, mainly because of too long symptom-onset-to-hospital intervals. Moreover, this strategy is effective for less than half of the patients treated within the therapeutic window. Early recanalization is the most powerful prognostic factor, and novel drugs or therapeutic strategies are primarily aimed at improving alteplase efficacy to rapidly and safely reopen the occluded arteries. Because IV alteplase-resistant thrombi are those with the largest clot burden, responsible for the most devastating brain-tissue infarctions, development of novel approved AIS therapies is an urgent priority. At present, in the absence of controlled trials, no valid recommendations can be made. However, the most promising emerging strategy is a combination of standard or low-dose IV alteplase with an intra-arterial (IA) procedure, including additional endovascular thrombolytic and/or mechanical clot retrieval. Notably, results of open trials using the IA route had relatively disappointing clinical outcomes, despite remarkable arterial recanalization rates. Controlled trials are urgently needed to evaluate strategies including an IA route. In addition, logistic and cost constraints will likely limit their routine use, even in industrialized countries. Combining of another IV drug and IV alteplase is a far less studied option, although much easier to implement. Add-on IV drugs could be an antiplatelet glycoprotein (GP) IIb/IIIa receptor antagonist, a direct thrombin inhibitor or a second thrombolytic agent, e.g. tenecteplase. However, neuroimaging to measure the clot burden and infarction size will probably be necessary to predict IV alteplase failure and the subsequent use of these eventual additional therapies.     

Alteplase Therapy for Acute Ischemic Stroke in Pregnancy: Two Case Reports and a Systematic Review of the Literature

Acute ischemic stroke (AIS) during pregnancy is a rare but serious complication. Intravenous alteplase is the only medication approved for hyperacute treatment of AIS; however, it has not been evaluated prospectively in pregnancy. Pregnancy was an exclusion criterion in prospective AIS studies and was only recently removed as a relative contraindication in the 2018 American Heart Association/American Stroke Association Stroke guidelines. Due to the exclusion of pregnant women from randomized controlled trials, the safety of fibrinolytic therapy in pregnant patients is not well established. In this review, we report the use of intravenous alteplase for AIS in two pregnant patients, with temporally associated clinical improvement and without complications to either the mother or fetus. Additionally, we summarize a systematic review of the literature for both intravenous and intra-arterial alteplase use for AIS in pregnant patients. A total of 31 cases met inclusion criteria for this review of assessment of safety and efficacy of alteplase use in pregnancy. Existing case reports and guidelines support the use of alteplase for AIS in pregnant patients without contraindications.     

Thrombolytics: drug interactions of clinical significance.

Thrombolytic agents activate plasminogen and induce a systemic fibrinolytic and anticoagulant state. Interaction of fibrinolysis with coagulation and platelet aggregation might be important for synergistic interactions with other antiplatelet or anticoagulant drugs. Thrombolytic agents are most often used in patients with coexisting cardiovascular medication, including various antihypertensives, beta-blocking agents, nitrates and aspirin (acetylsalicylic acid). In acute coronary syndromes, anticoagulants and antiplatelet compounds such as clopidogrel or glycoprotein IIb/IIIa receptor antagonists might be given. Inducers or inhibitors of the cytochrome P450 system are not reported to affect the pharmacokinetics of any thrombolytic agent. Since the elimination of the recombinant plasminogen activators saruplase and alteplase is dependent on liver blood flow, drugs affecting hepatic blood flow could theoretically affect the hepatic clearance of these agents. In fact, a reduction in thrombolytic activity has only been demonstrated for alteplase with nitroglycerin (glyceryl trinitrate). Pharmacodynamic interactions occur more often. The additive and beneficial effect of aspirin as concomitant therapy to thrombolysis has been demonstrated without excessive bleeding rates. No data are available on the interaction between ticlopidine or clopidogrel and thrombolytic agents in humans. Anticoagulation by heparin concomitantly with thrombolysis improves the patency rate of the occluded coronary vessel, but bleeding complications are seen more frequently. Although there has been no controlled study on the interaction between oral anticoagulants and thrombolytic agents, patients with myocardial infarction who were taking an oral anticoagulant before admission seem to be at higher risk for intracranial haemorrhage during thrombolytic therapy. Currently, no recommendations can be given for possible dose adjustment of thrombolytic therapy in patients receiving antiplatelet comedication. For comedication with heparin, it has been advised to monitor activated partial thromboplastin time frequently and to avoid values >2.5-fold normal. Patients receiving thrombolytic treatment should be monitored frequently for bleeding and the physician should be aware of any comedication exerting antiplatelet (e.g. aspirin, clopidogrel and ticlopidine) or anticoagulant (e.g. warfarin) effects.