Streptokinase. A pharmacoeconomic appraisal of its use in the management of acute myocardial infarction

Thrombolytic therapy with streptokinase and other agents reduces mortality and is now well accepted as the mainstay of revascularisation options for most patients after an acute myocardial infarction. Streptokinase is as efficacious as alteplase (recombinant tissue plasminogen activator; rt-PA) when given as a 3-hour infusion, anistreplase, reteplase and saruplase in reducing mortality. However, in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial, an accelerated alteplase regimen (1.5-hour infusion) plus intravenous heparin demonstrated a statistically significant 1% absolute mortality reduction compared with streptokinase plus heparin. Treatment with streptokinase is consistently clinically superior to conventional treatment and is cost effective: the marginal cost per year of life saved (cost/YLS) is less than $US/$Can20,000 (1990 or 1991 currency) assuming 5-year survival. In addition, streptokinase treatment is associated with fewer intensive care days and total days spent in hospital and a decrease in the use of intensive care services compared with conventional therapy. Importantly, the cost/YLS of treating older patients (70 to 80 years) with streptokinase is similar to that in younger patients (approximately $US22,000, 1990 currency). In 1 study, the cost of in-hospital treatment and associated 1-year follow-up costs did not differ significantly regardless of whether patients received streptokinase or anistreplase. In the most comprehensive cost-effectiveness analysis to date, GUSTO investigators determined that the incremental cost/YLS in patients who received the accelerated alteplase regimen instead of streptokinase was $US32,678 (1993 currency); the projected life expectancy was about 15 years. Thrombolytic therapy is generally more cost effective in patients at high risk than in those at low risk. The cost effectiveness of streptokinase is dependent on infarct location and time to treatment, but is more favorable in patients with anterior than inferior infarctions and those treated as soon as possible after symptom onset. There are as yet no comparative data to indicate a clinical benefit for one thrombolytic agent over another in patients treated more than 6 hours after symptom onset; therefore, in all likelihood, streptokinase will be preferred on the basis of cost minimisation. Streptokinase is associated with a slightly higher rate of severe bleeding than alteplase but a lower incidence of stroke. Although quality-of-life information comparing thrombolytics is unavailable, most patients who received streptokinase or alteplase rated their quality of life as high on the basis of results from time trade-off assessments and health surveys. In summary, streptokinase is undeniably cost effective compared with conventional treatment. It is up to individual healthcare systems to determine whether the mortality advantage and cost differential of the accelerated alteplase regimen over streptokinase, as seen in the GUSTO trial, are affordable and justifiable. However, it is important to realise that treatment options may be limited by healthcare resources; thus, streptokinase can be regarded as a cost-effective thrombolytic strategy which is both efficacious and affordable within the constraints of most healthcare budgets.     

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.     

Treatment of deep vein thrombosis with streptokinase.

From September 1962 to May 1972 145 patients with acute or subacute deep vein thrombosis confirmed by phlebography were treated with streptokinase. During the same period 42 patients considered unfit for thrombolytic therapy were treated with herapin and oral anticoagulants. The results, assessed by repeat phlebography, in 93 of the patients treated with streptokinase were compared with those in 42 patients treated with heparin. The age, sex, and severity of occlusion were roughly similar in both groups. Streptokinase treatment was successful in 42 per cent, partially successful in 25 per cent, and unsuccessful in 32 per cent of the 93 patients compared with none, 10 per cent, and 88 percent respectively in the 42 patients treated with heparin. Streptokinase was more effective when the thrombus was in proximal rather than calf veins. Thrombi of more than six days old were readily lysed. Plasma fibrinogen levels were below 0-8 g/1 (80 mg/100 ml) in nearly all patients successfully treated. The incidence of pulmonary embolism was no greater with streptokinase than with heparin treatment. Only prolonged follow-up would show whether thrombolytic treatment would be effective in preventing late complications of deep vein thrombosis such as chronic venous insufficiency.     

Optimal timing of thrombolytic therapy in acute ischaemic stroke

The clinical benefit of thrombolytic therapy for patients experiencing acute cerebral ischaemia has been demonstrated by both clinical trials and phase IV studies. However, such treatments must be initiated in a rapid manner, with treating physicians adhering to strict protocols designed to minimise delays and maximise safety. The efficacy of intravenous drug administration has been established with alteplase (recombinant tissue plasminogen activator; tPA) and ancrod, but only if these drugs can be administered within 3 hours of symptom onset. The use of alteplase beyond this timeframe, or outside of established protocols, may be hazardous. The use of alternative intravenous thrombolytic agents, such as streptokinase, also appears hazardous. Intra-arterial delivery of thrombolytic drugs such as pro-urokinase may extend clinical benefit to the 6-hour time frame.     

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.     

Evaluation and comparison of the adverse effects of streptokinase and alteplase.

The frequency and severity of adverse effects resulting from the administration of streptokinase and alteplase were determined in 126 consecutive patients who received standard dosages of these agents for the treatment of acute myocardial infarction. Evaluation was based on patient assessment by nursing staff, physicians, and the investigators before, during, and after thrombolytic administration. Overall, adverse effects occurred in 15 (41.7%) of 36 patients receiving streptokinase and 12 (13.3%) of 90 receiving alteplase (p = 0.001). No major bleeding or neurologic events were documented. Minor bleeding occurred in 13.9% and 7.8% of streptokinase and alteplase recipients, respectively (p = 0.47), and hypotension in 8 (22.2%) and 5 (5.6%), respectively (p = 0.01). The frequency of hypotension associated with streptokinase was significantly higher than that with alteplase. Thrombolytic-induced hypotension was easily managed and was not associated with sequelae.     

Quality aspects of fibrinolytic agents based on biochemical characterization.

The purity, composition and in vitro fibrinolytic activity of four commercially available fibrinolytic agents, alteplase (recombinant tissue plasminogen activator, rt-PA, Actilyse; CAS 105857-23-6), streptokinase, urokinase and anistreplase (ansioyl-plasminogen-streptokinase activator-complex, APSAC), have been compared in this investigation. The fibrinolytic activity was measured in an in vitro thrombolytic assay. In this assay a human blood thrombus is dissolved in an environment of human plasma. This assay is representative for the in vivo situation, where plasminogen activation is also a limiting step in thrombolysis. In the in vitro thrombolytic assay alteplase is about 10 times more effective in clot lysis than either streptokinase or urokinase and more than 300 times more active than anistreplase. In addition, the ratio of active ingredient to total protein content in the preparations was analysed by RP-HPLC, SDS-PAGE, GPC-HPLC and amino acid analysis. The portion of active ingredient per total protein was 99.9% for alteplase, 55% for anistreplase, 20% for urokinase and 1% for streptokinase. This demonstrates that alteplase is the only fibrinolytic agent tested which is essentially free of protein additives of human origine and potential contaminants associated therewith. The superior purity of alteplase compared to the other fibrinolytics was confirmed by SDS-PAGE, RP-HPLC, and HPLC-GPC. Significant levels of aggregates were detected in streptokinase and urokinase preparations, whereas alteplase and anistreplase were essentially free of aggregates. These data demonstrate that there are significant differences in composition, purity and in vitro activity between different fibrinolytic agents.     

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.     

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.     

Alteplase: new indication. Inadequately assessed in ischaemic stroke

(1) Alteplase is the first thrombolytic drug to be approved in France for the treatment of ischaemic stroke within three hours of symptom onset. (2) The clinical evaluation dossier contains nine placebo-controlled trials, of which six were relatively large. In the two NINDS trials (624 patients in total), treatment was started within the first three hours and it showed no survival benefit. Near-complete functional recovery was more frequent in the alteplase group than in the placebo group. In the two ECASS trials (620 and 800 patients) and the ATLANTIS trials (142 patients and 613 patients), treatment was started within the first six hours and it showed no significant benefit in terms of survival or functional recovery. (3) There are two meta-analyses of these trials. They confirm the lack of a survival benefit with alteplase. Using a combined endpoint, one meta-analysis showed that treating 1000 patients with alteplase prevented death or major disability (dependency) in 55 patients. The other meta-analysis underlined the importance of a short interval between the onset of symptoms and the beginning of treatment. (4) Intracranial haemorrhage is the most important adverse effect. One meta-analysis showed that alteplase caused 62 additional symptomatic intracranial haemorrhages (including 25 deaths) per 1000 treated patients. (5) Various retrospective subgroup analyses have tentatively identified subgroups of patients at a particularly high risk of adverse effects, but subgroup analyses provide only weak evidence. The patients most likely to benefit from alteplase, started within three hours of symptom onset, remain to be defined. (6) The current health infrastructure in France would allow only a small number of stroke patients to be treated with alteplase under the kind of conditions prevailing in clinical trials (imaging to confirm ischaemic stroke, and treatment very soon after the onset of symptoms). (7) In practice, there is a narrow margin between the wanted and unwanted effects of alteplase. This treatment should be used only by specialised teams and for strictly selected patients. Research must continue, particularly to identify those patients most likely to benefit from alteplase, and those most likely to be harmed in whom thrombolysis is contraindicated.     

Does impairment of renal and hepatic function influence the metabolism of thrombolytics in patients with myocardial infarction?

Thrombolytic agents activate plasminogen and induce a systemic fibrinolytic and anticoagulant state. Two thrombolytic drugs are used frequently in practice: streptokinase (SK) and alteplase (t-PA). Streptokinase mainly undergoes renal elimination with a half-life of 11-17 min, while alteplase is eliminating by the liver with a half-life of 4-6 min. Our goal was to examine whether renal and hepatic function influence the elimination and metabolism of thrombolytics and the efficacy of percutaneous coronary intervention (PCI) after using alteplase or streptokinase. 416 patients with myocardial infarction (MI) were treated from January 2001 to December 2003 (228 male and 189 female). Alteplase was used in 9 men and 6 women (mean age: 53.88 +/- 9.61 vs. 65.33 +/- 9.87 years, p = 0.07). Patients who underwent rescue PCI after administration of alteplase had slightly higher hepatic enzyme levels/alanine transaminase (ALT): 47.85 vs. 41.4 U/l; gamma-glutamyl transpeptidase (GGT): 69.5 vs. 44.8 U/l/. All patients treated with alteplase survived, rescue PCI was done in 8 cases. Streptokinase was used in 36 men and 28 women (mean age: 63.33 +/- 10.51 vs. 63 +/- 12.03 years, p = 0.9). We did not find a difference between serum creatinine levels of patients who received streptokinase and underwent PCI as compared to those who had not. Rescue PCI was done in 16 cases. 12 patients died in this group. In conclusion we have not found a significant correlation between the use of the thrombolytics and hepatic or renal function; this could indicate that such a slight impairment of liver and renal function does not influence pharmacokinetic properties of thrombolytics.     

Reteplase

Reteplase (Retavase) is a plasminogen activator, mimicking endogenous tissue plasminogen activator (t-PA), a serine protease, converting plasminogen to plasmin and thereby precipitating thrombolysis. It is a third-generation recombinant form of t-PA that operates in the presence of fibrin (i.e. it is fibrin specific). Reteplase can be administered as a bolus dose (nonweight-based) rather than an infusion, which promotes rapid and safe administration. The ease of administration of this reteplase dosage regimen (two 10U bolus doses, each over 2 minutes, 30 minutes apart) is conducive to prehospital initiation of thrombolytic treatment in patients with ST-segment elevation myocardial infarction (STEMI), which reduces the time to treatment, a critical factor in improving long-term survival. In large randomized clinical trials of patients with STEMI, reteplase was superior to alteplase for coronary artery patency (according to TIMI [thrombolysis in myocardial infarction] flow) at 60 and 90 minutes, but there was no significant difference between agents for mortality rate and incidence of intracranial bleeding. The 35-day mortality rates were equivalent for reteplase and streptokinase recipients; there was reduced incidence of some cardiac events with reteplase versus streptokinase, but a greater incidence of hemorrhagic stroke. Reteplase has also shown thrombolytic efficacy (in nonapproved indications) as a catheter-directed intra-arterial or intravenous infusion for peripheral vessel occlusions, as 5-minute bolus doses (in 1U increments) for acute ischemic stroke, as a low-dose solution for occluded catheters or grafts, and as an intravenous double bolus for massive pulmonary embolism. Across studies in these indications, the incidence of bleeding complications associated with reteplase treatment appeared to be similar to that associated with other thrombolytic agents. With its efficacy, and the ease of administration of the bolus doses potentially minimizing dosage errors when treatment is administered under time pressure, reteplase is a valuable option for pre- or in-hospital thrombolytic treatment in patients with STEMI, and is a useful thrombolytic for the treatment of the other thrombotic occlusive disorders described.     

阿替普酶与尿激酶溶栓治疗急性心肌梗死的疗效对比分析

目的 分析阿替普酶与尿激酶溶栓治疗急性心肌梗死的疗效及并发症.方法 选择我院2008年9月至2012年8月急性心肌梗死经溶栓治疗的248例患者.将所选患者因溶栓药物不同分为A组（阿替普酶）和B 组（尿激酶）,每组124例.观察两组血管总再通率、发病6 h内及6 h后溶栓血管再通率、死亡率、出血等不良反应及并发症.结果 发病6 h后溶栓,A、B组分别有28（70.0%）、18（47.4%）例再通;发病6 h内溶栓,A、B组分别有76（90.5%）、68（79.1%）例再通.两组比较差异有统计学意义（P〈0.05）.A组死亡2例（1.6%）,心力衰竭1例,心源性休克2例,脑出血1例,消化道出血3例,牙龈出血4例;B组死亡5例（4%）,心力衰竭1例,心源性休克3例,脑出血4例,消化道出血5例,牙龈出血8例.两组患者均未出现过敏反应,以上各项两组比较差异均无统计学意义（P〉0.05）.结论 阿替普酶具有血管开通率高、出血等并发症少、安全及使用方便等优点,是一种高效安全的治疗急性心肌梗死的溶栓药物.     

Incremental cost-effectiveness ratio of alteplase in patients with acute myocardial infarction in the French setting

On the basis of data collected from general hospital centres in France on 704 patients initially presenting with acute myocardial infarction, the mean 1-year cost of treatment was calculated to be 52,160 French francs (F) per patient (1994 values). This was independent of whether the patient received thrombolysis, and included all costs associated with initial hospitalisation including a stay in intensive care, cardiology or medical units, as well as rehospitalisations, revascularisation procedures and any drugs prescribed. When only those patients who survived the initial hospitalisation were considered, the mean cost of treatment was F58,184 per patient. Among patients who received thrombolysis during their initial hospitalisation, the respective mean 1-year costs were F74,684 per patient for those treated with alteplase and F64,866 per patient for those treated with streptokinase (p = 0.09). This nonsignificant difference can be explained by the higher cost of alteplase relative to that of streptokinase, the lower mortality rate associated with alteplase during the initial hospitalisation period (9.2% versus 10.6%) and the difference in the percentage of additional revascularisations required in the 2 treatment groups (32.8% versus 42.3%). Combining the pharmacoeconomic data collected in the French general hospital setting with incremental patient survival data stemming from the Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial showed that the incremental cost-effectiveness ratio of alteplase versus streptokinase amounted to F70128 per life-year saved for the total group, and F52035 per life-year saved for those patients who survived the initial period of hospitalisation.     

A single preoperative dose of cefazolin versus postoperative amoxicillin and gentamycin combination in prophylaxis of orthopaedic and traumatologic surgery.

The use of antibiotic prophylaxis was evaluated in 228 surgical patients. The patients were given either cefazolin preoperatively or amoxicillin + gentamycin postoperatively in a randomized fashion to determine whether cefazolin would demonstrate an advantage over amoxicillin + gentamycin with respect to protection against postoperative wound infection, systemic infection and cost. We also tried to find out if the inflation of a tourniquet would interfere in the incidence of wound infection. Major postoperative wound infections were reduced in the cefazolin treated group (2.56 per cent versus 4.50 per cent). There also was a reduction in minor postoperative wound infections in the cefazolin group when it was compared with the amoxicillin + gentamycin group (6.83 per cent, 13.51 per cent, respectively). No systemic infection was seen in either group. There was no difference between the patients on whom were used tourniquets or not. Analysis of patients' charges suggested that 68.75% of the cost of preoperative antibiotic prophylaxis might be saved by limiting the duration of prophylactic drug administration by cefazolin.     

小剂量阿替普酶治疗老老年急性心肌梗死的疗效

目的探讨阿替普酶静脉溶栓治疗急性心肌梗死老老年患者的疗效及并发症发生情况。方法将95例老老年AMI患者随机分为观察组45例和对照组50例,观察组应用小剂量阿替普酶治疗,对照组给予尿激酶(UK)静脉溶栓。观察两组疗效及出血并发症发生情况。结果观察组、对照组的冠状动脉再通率分别为82.2%、50.0%;患者在发病3 h内静脉溶栓再通率分别为85.7%、56.7%(P<0.01);4周病死率分别为4.4%、6.0%(P>0.05)。结论小剂量阿替普酶静脉溶栓治疗老老年AMI临床疗效好,血管再通率高,尤其在发病3 h之内进行溶栓治疗效果更佳,是一种安全有效的溶栓剂。     

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.     

Streptokinase and lifestyle outcome in survivors of myocardial infarction.

Clinical and lifestyle parameters were assessed in 145 patients who were randomised in a double blind study comparing streptokinase or placebo given within four hours of the onset of ischaemic chest pain. Sixty-six percent of patients were in paid employment at the time of their infarct and 79% returned to paid employment. Patients who received streptokinase returned to work 17 days earlier (p less than 0.05) and returned to sport and leisure activities 33 days earlier (p less than 0.05) than those who received placebo. Those who had received streptokinase also tended to leave hospital earlier (0.8 days, p = 0.07). There were no differences in angioplasty or coronary surgery rates or the incidence of reinfarction in the first year (8%). Total community costs were reduced in the patients who received thrombolytic therapy. These findings have important implications in the benefit:cost analysis of thrombolytic therapy.     

Alteplase versus urokinase in restoring blood flow in hemodialysis-catheter thrombosis.

The effectiveness of alteplase and urokinase in restoring adequate hemodialysis blood-flow rates was examined. A retrospective review of the medical records of hemodialysis patients with central venous catheters receiving alteplase or urokinase for presumed catheter thrombosis between June 1997 and December 2000 was conducted. Patients received 1 mL of alteplase 1 mg/mL or 1 mL of urokinase 5000 units/mL in each catheter port. The choice of the thrombolytic agent was left to the prescriber. Effectiveness of thrombolysis was defined as achieving a posttreatment hemodialysis blood-flow rate of > 300 mL/min, maintained for at least 30 minutes during the dialysis session. Inclusion criteria included adherence to the thrombolytic protocol and the inability to achieve a hemodialysis blood-flow rate of > 300 mL/min during the first 60 minutes of the hemodialysis session despite at least one attempt to reposition the catheter. Both thrombolytic agents significantly increased the hemodialysis blood-flow rates. Patients with alteplase-treated catheters were twice as likely to achieve hemodialysis blood-flow rates of > 300 mL/min (p = 0.0134) and were more likely to complete hemodialysis during that session (93% versus 70%, p = 0.0234). The percentage of functioning catheters at a subsequent hemodialysis session did not significantly differ between groups (p = 0.0806). The majority of patients in both treatment groups required no further interventions. Hemodialysis blood-flow rates increased after either alteplase 1 mg/mL per port or urokinase 5000 units per port was used to clear presumed catheter thrombosis. Alteplase was more likely than urokinase to result in a hemodialysis blood-flow rate of > 300 mL/min.     

Should Thrombolytic Therapy Be Used in Patients with Pulmonary Embolism?

More than thirty years have passed since streptokinase was first shown to dissolve pulmonary arterial thrombi and normalize pulmonary artery pressure in patients with acute pulmonary embolism (PE). Following the initial observations, a number of controlled clinical trials confirmed that treatment with streptokinase, urokinase or alteplase recombinant tissue plasminogen activator is superior to heparin alone in improving angiographic and hemodynamic parameters in these patients. At present, there is consensus that patients with massive PE presenting with overt right ventricular failure (clinical instability and cardiogenic shock) should promptly be treated with thrombolytic agents, since they are at a particularly high risk for death or life-threatening complications during the acute phase. At the other end of the clinical spectrum, thrombolysis for PE is not indicated in the absence of right ventricular dysfunction. In fact, the prognosis of patients with small pulmonary emboli (not affecting pulmonary artery pressure and right ventricular afterload), is excellent and, as a result, the bleeding risks of thrombolysis may outweigh the potential benefits of this treatment. Currently, the thrombolysis debate focuses on patients with submassive PE, i. e. those who present with signs of subclinical, impending right heart failure. Recently, a number of clinical studies demonstrated that these patients are also at risk for an adverse clinical outcome. Besides the established prognostic value of echocardiography, evidence is now accumulating that cardiac troponins and, possibly, pro-brain natriuretic peptide levels also may permit an early, reliable risk stratification of patients with PE and particularly help identify submassive PE in the presence of apparent clinical stability. Recently, the Management Strategies and Prognosis of Pulmonary Embolism-3 trial examined the effects of thrombolysis on the prognosis of patients with acute submassive PE. The study patients were randomly assigned to receive alteplase (100mg over 2 hours) or placebo with concomitant heparin anticoagulation. Although in-hospital mortality was low in both the alteplase and the heparin-only group, this study showed for the first time that early treatment with alteplase can improve the clinical course of patients with acute submassive PE, and particularly reduce the need for emergency escalation of treatment. Importantly, no fatal or cerebral bleeding episodes were observed in the alteplase group. This fact indicates that use of thrombolysis in PE can be safe in patients who have no contraindications to this type of treatment. Based on these data, the indications for thrombolysis can be extended to include patients presenting with submassive PE.