Introduction: Acute leg ischemia is one of the most challenging and dangerous conditions in vascular surgical practice and carries a high risk of amputation and death when left untreated. This article provides an overview of the currently held opinions on the role of catheter-based thrombolytic therapy in patients with acute leg ischemia. Methods: A systematic review of literature from 1980 to 2009 was performed. The literature analyzed included randomized trials, large single-center case series, and review articles. Results: Three large randomized trials and 14 review articles were identified. Pharmacologic aspects and the results of thrombolytic therapy, as well as indications, contraindications, and complications are described. Conclusions: Catheter-directed thrombolysis can be considered a complementary and not a competing technology with surgical or percutaneous revascularization, with an acceptably low complication rate. © 2010 Society for Vascular Surgery.

Appropriate use of a thrombolytic agent may save 20 to 30 lives per 1000 treatments. Thrombolysis should be considered in all patients presenting with cardiac chest pain lasting more than 30 minutes for up to 12 hours after symptom onset. ECG criteria include ST elevation of at least 1 mm in limb leads and/or at least 2 mm in two or more adjacent chest leads or left bundle branch block. There is no upper age limit. All patients should also receive oral aspirin and subcutaneous (intravenous with rt-PA) heparin. Other adjuvant treatments have been reviewed previously in this journal. Streptokinase is the drug of choice except where there is persistent hypotension, previous streptokinase or APSAC at any time, known allergy to streptokinase, or a recent proven streptococcal infection. In these circumstances the patient should receive rt-PA. Additional indications for rt-PA, based on subset analysis by the GUSTO investigators, include patients with ALL of the following: age less than 75 years, presentation within four hours of symptom onset, and ECG evidence of anterior acute myocardial infarction. Treatment should be initiated as soon as possible. The greatest benefit is observed in patients treated early, pain to treat intervals of less than one hour make possible mortality reductions of nearly 50%. "When" matters more than "where": fast tracking to the CCU is one option but A&E initiated thrombolysis is feasible and timely. Prehospital thrombolysis is appropriate in certain geographical situations. The development of practical guidelines for thrombolysis represents the most comprehensive example of evidence based medicine. Streptokinase was first shown to influence outcome in acute myocardial infarction nearly 40 years ago. More recently alternative regimes have been evaluated in several prospective randomised controlled trials yielding pooled data on nearly 60,000 patients. However, systematic review of cumulative data reveals a statistically significant mortality gain for intravenous streptokinase over placebo which could have been identified as early as 1971-at least 15 years before it became generally used in clinical practice.

BACKGROUND:

Most strokes are due to blockage of an artery in the brain by a blood clot. Prompt treatment with thrombolytic drugs can restore blood flow before major brain damage has occurred and improve recovery after stroke in some people. Thrombolytic drugs, however, can also cause serious bleeding in the brain, which can be fatal. One drug, recombinant tissue plasminogen activator (rt-PA), is licensed for use in selected patients within 4.5 hours of stroke in Europe and within three hours in the USA. There is an upper age limit of 80 years in some countries, and a limitation to mainly non-severe stroke in others. Forty per cent more data are available since this review was last updated in 2009.

OBJECTIVES:

To determine whether, and in what circumstances, thrombolytic therapy might be an effective and safe treatment for acute ischaemic stroke.

SEARCH METHODS:

We searched the Cochrane Stroke Group Trials Register (last searched November 2013), MEDLINE (1966 to November 2013) and EMBASE (1980 to November 2013). We also handsearched conference proceedings and journals, searched reference lists and contacted pharmaceutical companies and trialists.

SELECTION CRITERIA:

Randomised trials of any thrombolytic agent compared with control in people with definite ischaemic stroke.

DATA COLLECTION AND ANALYSIS:

Two review authors applied the inclusion criteria, extracted data and assessed trial quality. We verified the extracted data with investigators of all major trials, obtaining additional unpublished data if available.

MAIN RESULTS:

We included 27 trials, involving 10,187 participants, testing urokinase, streptokinase, rt-PA, recombinant pro-urokinase or desmoteplase. Four trials used intra-arterial administration, while the rest used the intravenous route. Most data come from trials that started treatment up to six hours after stroke. About 44% of the trials (about 70% of the participants) were testing intravenous rt-PA. In earlier studies very few of the participants (0.5%) were aged over 80 years; in this update, 16% of participants are over 80 years of age due to the inclusion of IST-3 (53% of participants in this trial were aged over 80 years). Trials published more recently utilised computerised randomisation, so there are less likely to be baseline imbalances than in previous versions of the review. More than 50% of trials fulfilled criteria for high-grade concealment; there were few losses to follow-up for the main outcomes.Thrombolytic therapy, mostly administered up to six hours after ischaemic stroke, significantly reduced the proportion of participants who were dead or dependent (modified Rankin 3 to 6) at three to six months after stroke (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.78 to 0.93). Thrombolytic therapy increased the risk of symptomatic intracranial haemorrhage (OR 3.75, 95% CI 3.11 to 4.51), early death (OR 1.69, 95% CI 1.44 to 1.98; 13 trials, 7458 participants) and death by three to six months after stroke (OR 1.18, 95% CI 1.06 to 1.30). Early death after thrombolysis was mostly attributable to intracranial haemorrhage. Treatment within three hours of stroke was more effective in reducing death or dependency (OR 0.66, 95% CI 0.56 to 0.79) without any increase in death (OR 0.99, 95% CI 0.82 to 1.21; 11 trials, 2187 participants). There was heterogeneity between the trials. Contemporaneous antithrombotic drugs increased the risk of death. Trials testing rt-PA showed a significant reduction in death or dependency with treatment up to six hours (OR 0.84, 95% CI 0.77 to 0.93, P = 0.0006; 8 trials, 6729 participants) with significant heterogeneity; treatment within three hours was more beneficial (OR 0.65, 95% CI 0.54 to 0.80, P < 0.0001; 6 trials, 1779 participants) without heterogeneity. Participants aged over 80 years benefited equally to those aged under 80 years, particularly if treated within three hours of stroke.

AUTHORS' CONCLUSIONS:

Thrombolytic therapy given up to six hours after stroke reduces the proportion of dead or dependent people. Those treated within the first three hours derive substantially more benefit than with later treatment. This overall benefit was apparent despite an increase in symptomatic intracranial haemorrhage, deaths at seven to 10 days, and deaths at final follow-up (except for trials testing rt-PA, which had no effect on death at final follow-up). Further trials are needed to identify the latest time window, whether people with mild stroke benefit from thrombolysis, to find ways of reducing symptomatic intracranial haemorrhage and deaths, and to identify the environment in which thrombolysis may best be given in routine practice.

Objectives: Deep venous thromboses (DVTs) are a significant cause of morbidity and mortality in the general and inpatient population. Current anticoagulation therapy is efficient in reducing thrombus propagation but does not contribute to clot lysis or prevention of post-thrombotic limb syndrome. Catheter directed thrombolysis (CDT) is an alternative method for treating DVTs but there is no consensus regarding indications for its use. Data sources: PubMed and Cochrane library were searched for all articles on deep vein thrombosis and thrombolysis. Review method: Articles presenting data on DVT thrombolysis, DVT anticoagulation, mechanical thrombectomy, venous stenting and May-Thurner's syndrome were considered for inclusion in the review. Results: CDT reduced clot burden, DVT recurrence and may prevent the formation of post-thrombotic syndrome. Indications for its use include younger individuals with a long life expectancy and few co-morbidities, limb-threatening thromboses and proximal ilio-femoral DVTs. There is a marked lack of randomised controlled trials comparing CDT-related mortality and long term outcomes compared to anticoagulation alone. The effectiveness of combined pharmaco-mechanic thrombectomy, although promising, need to be further investigated, as is the role of caval filters in preventing DVT-associated pulmonary emboli. Conclusions: These results suggest that the outcome of CDT in DVT management are encouraging in selected patient cohorts, but further evidence is required to establish longer term benefits and cost-effectiveness. © 2009 European Society for Vascular Surgery.

OBJECTIVES:

To determine whether a specialist cardiac nurse would improve delay to thrombolysis in acute myocardial infarction (MI).

SUBJECTS:

Patients presenting with chest pain to a district general hospital.

METHOD:

Comparison of: a) door-to-needle times of patients with 'definite' MI when the nurse was on and off duty (15 months) and prior to her employment (3 months); b) pain-to-needle times for definite MI; and c) door-to-needle times of patients without definite MI on first electrocardiogram (ECG) but who subsequently qualified for thrombolysis.

RESULTS:

Of 365 patients included in the study, 289 had definite MI. Before the appointment of a thrombolysis nurse, door-to-needle times were 0% at 30 minutes, 7% at 45 minutes and 34% at 60 minutes. Since the appointment, with the nurse on-duty, they have improved to 58%, 91% and 100% respectively, a saving of 36 minutes in median door-to-needle time (p = 0.0001). There was a median saving of 95 minutes in pain-to-needle times with the thrombolysis nurse on duty compared with off duty (p = 0.0001). Finally, with the nurse on duty there was also a saving of 36 minutes in median door-to-needle time in patients in whom the first ECG was non-diagnostic for MI (p = 0.02).

CONCLUSIONS:

A thrombolysis nurse produced a dramatic improvement in median door-to-needle and pain-to-needle times in patients presenting with definite MI. This would lead to an additional 41 lives saved at 30 months per 1,000 patients treated. With 24-hour thrombolysis nurse cover, this would potentially lead to 8 additional lives saved at 30 months at a cost of 12,300 Pounds each. There was also a striking improvement in door-to-needle times for patients presenting with a non-diagnostic first ECG who subsequently qualified for thrombolysis.

BACKGROUND :

Recent evidence has suggested that intra-arterial thrombolysis may provide benefit beyond intravenous thrombolysis in ischemic stroke patients. Previous meta-analyses have only compared intra-arterial thrombolysis with standard treatment without thrombolysis. The objective was to review the benefits and harms of intra-arterial thrombolysis in ischemic stroke patients.

METHODS :

We undertook a meta-analysis of randomized controlled trials comparing the efficacy and safety of intra-arterial thrombolysis with either standard treatment or intravenous thrombolysis following acute ischemic stroke. Primary outcomes included poor functional outcomes (modified Rankin Scale 3-6), mortality, and symptomatic intracranial hemorrhage. Study quality was assessed, and outcomes were stratified by comparison treatment received.

RESULTS :

Four trials (n = 351) comparing intra-arterial thrombolysis with standard treatment were identified. Intra-arterial thrombolysis reduced the risk of poor functional outcomes (modified Rankin Scale 3-6) [relative risk (RR) = 0·80; 95% confidence interval = 0·67-0·95; P = 0·01]. Mortality was not increased (RR = 0·82; 95% confidence interval = 0·56-1·21; P = 0·32); however, risk of symptomatic intracranial hemorrhage was nearly four times more likely (RR = 3·90; 95% confidence interval = 1·41-10·76; P = 0·006). Two trials (n = 81) comparing intra-arterial thrombolysis with intravenous thrombolysis were identified. Intra-arterial thrombolysis was not found to reduce poor functional outcomes (modified Rankin Scale 3-6) (RR = 0·68; 95% confidence interval = 0·46-1·00; P = 0·05). Mortality was not increased (RR = 1·12; 95% confidence interval = 0·47-2·68; P = 0·79); neither was symptomatic intracranial hemorrhage (RR = 1·13; 95% confidence interval = 0·32-3·99; P = 0·85). Differences in time from symptom onset-to-treatment and type of thrombolytic administered were found across the trials.

CONCLUSIONS :

This analysis finds a modest benefit of intra-arterial thrombolysis over standard treatment, although it does not find a clear benefit of intra-arterial thrombolysis over intravenous thrombolysis in acute ischemic stroke patients. However, few trials, small sample sizes, and indirectness limit the strength of evidence.

BACKGROUND:

Despite proven advantages of primary percutaneous coronary intervention (PCI), thrombolysis remains the first line treatment for ST-elevation myocardial infarction (STEMI) worldwide. Management of patients with failed thrombolysis is still debated, and data from existing randomized controlled trials are conflicting.

AIM:

To compare the risk/benefit profile of repeat thrombolysis (RT) vs. rescue PCI in patients with failed thrombolysis.

METHODS:

Search of BioMedCentral, CENTRAL, mRCT and PubMed for randomized controlled trials comparing rescue PCI vs. conservative therapy and/or RT vs. conservative therapy. Outcomes of interest assessed by adjusted indirect meta-analysis: major adverse events (MAE, defined as the composite of overall mortality and re-infarction), stroke, congestive heart failure (CHF), major bleeds (MB), and minor bleeds. Overall mortality and re-infarction have been also analysed individually.

RESULTS:

Eight trials were included (1318 patients). Follow-up ranged from 'in-hospital' to 6 months. No significant difference was found for the risk of MAE [OR 0.93(0.26-3.35), P = 0.4], overall mortality [OR 1.01(0.52-1.95), P = 0.15], stroke [OR 5.03(0.64-39.1), P = 0.58] and CHF [OR 0.74(0.28-1.96), P = 0.6]. Compared with conservative therapy, rescue PCI was associated with a 70% reduction in the risk of re-infarction [OR 0.32(0.14-0.74), P = 0.008], number needed to treat 17. No difference in terms of MB was found [OR 0.5(0.1-2.5), P = 0.09], while a greater risk of minor bleeds was observed with rescue PCI [OR 2.48(1.08-5.7), P = 0.04], number needed to harm 50.

CONCLUSION:

Although the observed benefit is modest, these data support the use of PCI after failed thrombolysis.

PURPOSE:

To report a single-center clinical experience with ultrasound-enhanced thrombolysis in the treatment of both arterial and venous thromboses.

METHODS:

From January 2005 to June 2006, 33 patients (23 men; age range 39-90 years) with 36 occlusions were treated using ultrasound-enhanced thrombolytic therapy for acute and chronic arterial and venous occlusions. After diagnostic angiography, the occlusions were crossed with an appropriately sized Lysus infusion catheter for infusion of urokinase (80,000-120,000 IU/h).

RESULTS:

Technical success and complete lysis was achieved in 96% of the arterial and 83% of the venous occlusions. Two patients with chronic occlusions (one superficial femoral artery and one iliac vein) were refractory to lytic therapy. Average time for complete lysis was 16.4 hours (range 3-25) for arterial occlusions and 21.2 hours (range 6-43) in patients with deep vein thrombosis.

CONCLUSION:

Successful clot lysis can be achieved with a high rate of success in a shorter time than conventional thrombolysis using ultrasound-enhanced thrombolysis in both acute and chronic arterial and venous thromboses.

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PURPOSE:

To review all available literature on catheter-directed ultrasound-accelerated thrombolysis for peripheral artery occlusions, stroke, deep venous thrombosis, and pulmonary embolism.

METHODS:

A systematic literature search was performed, using MEDLINE, EMBASE and Cochrane databases. A total of 77 reports focusing on catheter-delivered ultrasound-accelerated thrombolysis were identified.

RESULTS:

Experimental studies show that high intensity ultrasound may induce thrombolysis, with and without the addition of plasminogen activators, mainly by acoustic cavitation and mechanical disruption, while low intensity, high frequency ultrasound waves may actually enhance plasmin-mediated thrombolysis. In a total of 340 clinical cases of various thromboembolic conditions, catheter-directed ultrasound-accelerated thrombolysis was related to rapid revascularization and a reduction in treatment time, drug dosage, hospitalization time, and possibly major bleeding complications compared to standard thrombolysis. Reported complication rates, including bleeding and embolization, were low.

CONCLUSION:

Ultrasound enhanced thrombolysis seems to be a promising concept in the treatment of various thromboembolic conditions. The technique has shown to be safe and efficacious in vitro, in vivo, and in clinical studies. Randomized controlled trials are warranted and should be awaited before considering catheter-directed ultrasound-accelerated thrombolysis as a new standard treatment.