A comparison of thrombolytic therapy with operative revascularization in the initial treatment of acute peripheral arterial ischemia. Prospective randomized trial of high-dose bolus versus low-dose tissue plasminogen activator infusion in the management of acute limb ischaemia. Thrombolysis Study Group. SYNTHESIS expansion: design of a nonprofit, pragmatic, randomized, controlled trial on the best fast-track endovascular treatment vs. standard intravenous alteplase for acute ischemic stroke. Surgical treatment versus thrombolysis in acute arterial occlusion: a randomised controlled study. Comparison of intravenous and intra-arterial urokinase thrombolysis for acute ischaemic stroke.
Despite the widespread use of intraarterial thrombolytic therapy for peripheral arterial occlusive disease, a randomized study comparing its efficacy with that of operative intervention has never been performed. This study evaluates the potential of intraarterial urokinase infusion to provide clinical benefits in patients with acute peripheral arterial occlusion.
                Patients with limb-threatening ischemia of less than 7 days' duration were randomly assigned to intraarterial catheter-directed urokinase therapy or operative intervention. Anatomic lesions unmasked by thrombolysis were treated with balloon dilation or operation. The primary end points of the study were limb salvage and survival.
                A total of 57 patients were randomized to the thrombolytic therapy group, and 57 patients were randomized to the operative therapy group. Thrombolytic therapy resulted in dissolution of the occluding thrombus in 40 (70%) patients. Although the cumulative limb salvage rate was similar in the two treatment groups (82% at 12 months), the cumulative survival rate was significantly improved in patients randomized to the thrombolysis group (84% vs 58% at 12 months, p = 0.01). The mortality differences seemed to be primarily attributable to an increased frequency of in-hospital cardiopulmonary complications in the operative treatment group (49% vs 16%, p = 0.001). The benefits of thrombolysis were achieved without significant differences in the duration of hospitalization (median 11 days) and with only modest increases in hospital cost in the thrombolytic treatment arm (median $15,672 vs $12,253, p = 0.02).
                Intraarterial thrombolytic therapy was associated with a reduction in the incidence of in-hospital cardiopulmonary complications and a corresponding increase in patient survival rates. These benefits were achieved without an appreciable increase in the duration of hospitalization and with only modest increases in hospital cost, suggesting that thrombolytic therapy may offer a safe and effective alternative to operation in the initial treatment of patients diagnosed with acute limb-threatening peripheral arterial occlusion. Accelerated thrombolysis with high-dose bolus tissue plasminogen activator (tPA) may enable patients with more severe acute leg ischaemia to be treated without recourse to surgery. This study was a randomized comparison of two thrombolytic regimens.
                One hundred patients with acute leg ischaemia of less than 30 days' duration were randomized to receive either high-dose bolus tPA (three doses of 5 mg over 30 min, then 3.5 mg/h for up to 4 h, then 0.5-1.0 mg/h) or conventional low-dose tPA (0.5-1.0 mg/h). The groups were well matched for age, cardiovascular risk factors, duration and severity of ischaemia, site, cause and length of arterial occlusion.
                The median duration of infusion in the high-dose group was 4.0 (range 0.25-46) h compared with 20 (range 2-46) h for low-dose infusion (P < 0.0001). Successful thrombolysis was achieved in 45 of 49 high-dose and 39 of 44 low-dose infusions but significantly more adjunctive procedures were required following high-dose bolus infusion (26 versus 16 patients) (P = 0.002). Thirty days after treatment was commenced, limb salvage was achieved in 39 of 49 patients in the high-dose group compared with 37 of 44 who had a low-dose infusion of tPA. Six and two patients respectively required amputation. Four patients in the high-dose group and five in the low-dose group died. Three patients in each group suffered a major haemorrhage and one in the low-dose group had a stroke.
                High-dose bolus therapy significantly accelerated thrombolysis with tPA without compromising outcome. Some 50 per cent of patients were treated within 4 h enabling thrombolysis to be used as primary therapy for patients with acute critical ischaemia. Rationale Reperfusion in ischemic stroke can be pursued by either systemic intravenous thrombolysis or endovascular treatment. However, systemic intravenous thrombolysis with alteplase within 4·5 h of symptom onset in selected patients is the only medication of proven efficacy. No randomized-controlled trials have so far compared the two modalities. To explore this, after a pilot phase, we started the SYNTHESIS Expansion trial. Aims To determine whether endovascular treatment (i.e., intra-arterial thrombolysis with alteplase - if necessary, associated to or substituted by mechanical clot disruption and/or retrieval) compared with systemic intravenous thrombolysis with alteplase, administered according to European labelling, increases the proportion of independent survivors at three-months. Design SYNTHESIS Expansion is an open-label, multicenter randomized-controlled trial, with blinded follow-up. Eligibility applies to; patients with symptomatic ischemic stroke, seen within 4·5 h of onset; being able to initiate intravenous alteplase immediately, and endovascular treatment as soon as possible (not later than six-hours of stroke onset). The study is pragmatically based on the 'uncertainty principle' between endovascular treatment and systemic intravenous thrombolysis for patients eligible for intravenous alteplase. There are no prespecified clinical or instrumental criteria to further select a patient, although investigators are left free to use them. Enrollment will be completed with 350 randomized patients. Primary analysis is on an intent-to-treat basis. Study outcomes Primary: modified Rankin scale score of 0 or 1 at three-months. Secondary: neurological deficit seven-days after thrombolysis and the safety of the procedure on the basis of events reported within seven-days following thrombolysis - symptomatic cerebral hemorrhage, fatal and nonfatal stroke, death from any cause, neurological deterioration.
                © 2011 The Authors. International Journal of Stroke © 2011 World Stroke Organization. Thrombolytic treatment has been tried in various forms for acute limb ischaemia with varying degrees of success but is also often accompanied by bleeding problems. The present investigation compares the effect of surgical thrombectomy (TE) and thrombolysis (TL) using recombinant tissue plasminogen activator (rt-PA). Twenty patients with a need for intervention owing to ischaemia lasting more than 24 h but less than 14 days were included. Patients randomised to TE were operated under epidural anaesthesia and patients in the TL group received 30 mg rt-PA during a 3 h period through a catheter placed into the thrombus and advanced as lysis was achieved. Thrombectomy resulted in an immediate restitution of blood flow in six out of nine cases, in three cases a bypass procedure was performed, and one of these failed with a resultant amputation. Thrombolysis gave a good primary result in six cases which lasted in four of them. Three had a subsequent percutaneous transluminal angioplasty. Partial lysis was seen in two cases and a further two failed. Five went to surgery with three bypass and two fogarty procedures being necessary. There was no hospital mortality and there were no bleeding complications due to the rt-PA treatment in this series. In 19 out of 20 patients the circulation was re-established. Appropriate handling of acute ischaemic conditions implies the use of both thrombolysis and appropriate surgical procedures, including distal bypass grafts. Intravenous fibrinolysis (IVF) with rt-PA (alteplase) provides significant benefits in acute ischaemic stroke when it is given within the first three hours following stroke onset. Intra-arterial fibrinolysis (IAF) with pro-urokinase in PROACT II study provides quite the same benefit in the first 6 hours. IVF and IAF have never been compared. To compare the efficacy and safety of IVF and IAF with urokinase given within the first 6 hours of acute ischaemic stroke. Patients fulfilling the selection criteria were randomly assigned to receive urokinase 900,000 units via intravenous or intra-arterial routes. This randomised monocentre study was done between December 1995 and August 1997. The primary outcome was defined as the number of patients with a modified Rankin score of 2 or less. Secondary outcomes included mortality, frequency of symptomatic intracranial haemorrhage (SIH), neurological and functional scores. Fourteen patients were given IVF and 13 IAF. The study was terminated by the National Health Authorities when 27 patients had been included because of the mortality rate. Seven patients (26%) died, 4 in the IV group (oedematous infarct in 3 and recurrence in 1), 3 in the IA group (SIH in 2, and oedematous infarct in 1). Patients given IVF were treated significantly earlier (4:16 h vs 5:24 h; p=.007). Although IA patients showed greater and earlier improvement there was no significant difference in primary and secondary outcomes. Because of premature termination, the trial was too small to provide any reliable and conclusive results. Intra-arterial fibrinolysis began significantly later than IV fibrinolysis but it gave non-significantly better results in this prematurely terminated study.
Implications for practice
 

Thrombolysis should be reserved for patients with limb threatening ischaemia, due to the high risk of haemorrhage or death. Greater benefit is seen when the thrombolytic agent is delivered into the thrombus. Systemic intravenous thrombolysis is less effective than intra-arterial thrombolysis and is associated with an increase in bleeding complications.  'High dose' and 'forced infusion' techniques, or adjunctive agents such as platelet glycoprotein IIb/IIIa inhibitors may speed up thrombolysis, but these are not accompanied by lower amputation rates or a decreased need for adjunctive endovascular or surgical procedures. 'Low dose continuous infusion', following initial lacing of the thrombus with a high dose of the thrombolytic agent, is the least labour intensive technique. 


Implications for research



Only large multicentre trials with carefully controlled inclusion criteria will be sufficiently powerful to demonstrate genuine benefit for a particular thrombolytic regime.