Low-dose Intra-arterial Thrombolysis Research Articles

Endovascular treatment in acute ischemic stroke: collaboration between neurologists and cardiologists in a single center

Abstract Background Several randomized trials have indicated a benefit from endovascular therapy in acute ischemic stroke (AIS) patients. In some centers, interventional cardiologists with previous large carotid stenting experience can play significant role for this treatment. Objectives We present retrospective analysis of prospectively collected data of endovascular treatment of stroke (EVTS) performed by interventional cardiologists in collaboration with neurologists in 46 patients in single center. Methods Between 2014 and 2017 46 consecutive AIS patients underwent EVT, men 69.7% (7 with posterior circulation stroke and 5 with wake-up stroke), with mean age 64.6±13 years and average National Institutes of Health Stroke Scale (NIHSS) score of 12.2±5 at presentation. During the same period of time 20 patients, 16 men, at mean age 69.4±12, and NIHSS score 11.8±7 received IVT. In the EVT group two methods were applied: Method 1, Supraselective intra-arterial thrombolysis (IAT) alone or IAT plus balloon angioplasty (PBA); Method 2, Aspiration with Penumbra aspiration system (PAS) or Combination of PAS plus low dose IAT. Results The mean symptoms onset-to-treatment (needle) time (ONT) in the EVT group was 221.7±121.5 minutes, and 185.5±34.9 in the IVT group (p=0.19T). Conscious sedation and local anesthesia was used in 84.7% of the patients (40), general anesthesia in 15.2%; preprocedural MRI was performed in 58.7% and CT in 71.7% of the patients. In the EVT group successful reperfusion (TICI 2b-3 flow) was achieved in 35 (76.1%) patients: in 73.9% with Method 1 and in 86.7% with Method 2 (p=0.44). Poor or no recanalization (TICI 0–1-2a) was observed in 26.1%. Twenty six of 46 patients (56.5%) treated with endovascular methods and respectively 9 (45%) with IVT demonstrated favorable clinical outcome of mRS score 0–2 at 90 days (p=0.91). The overall 3-month mortality was 15.2%, 13% after EVT and 20% after IVT (p=0.48). Conclusions Our initial experience with EVT of AIS performed by trained cardiologists with carotid experience is encouraging, with a relatively moderate to high rate of successful angiographic recanalization and good clinical results. Funding Acknowledgement Type of funding source: None

Therapeutic application of contrast-enhanced ultrasound and low-dose urokinase for thrombolysis in a porcine model of acute peripheral arterial occlusion

The addition of local ultrasound (US) with a contrast agent to standard intra-arterial thrombolysis can accelerate the thrombolytic treatment of stroke and myocardial infarction. The contrast agent consists of microsized gas-filled bubbles that collapse when exposed to US, causing destabilization of the clot and making the clot surface more susceptible to fibrinolytics. In this study, we investigated the effect of additional US and microbubbles on standard low-dose intra-arterial thrombolysis in a porcine model of extensive peripheral arterial occlusion. Extensive arterial thrombosis was induced in 10 pigs in the 4-cm external iliac artery by clamping and injection of 100 IU of bovine thrombin. A transcutaneous laser Doppler flow probe and an ultrasonic perivascular flow probe assessed microcirculation and arterial flow respectively. The urokinase-only (UK) group (n = 4) received standard thrombolytic therapy: intra-arterial bolus injection of 500,000 IU, followed by a continuous low-dose urokinase (50,000 IU/h) infusion through an intra-arterial catheter and local intermittent application of US, 1 second on, 5 seconds off, to visualize vascular patency during the first hour of therapy and to ensure microbubbles replenished the proximal portion of the occluded artery. The urokinase plus microbubbles (UK+) group (n = 6) received the same urokinase therapy with a concomitant intravenous infusion of microbubbles and local intermittent application of US. The contrast infusion protocol consisted of a bolus of two vials of 5 mL in the first 15 minutes and then three times 5 mL slowly hand-injected continuously during the next 45 min. After 3 hours of therapy, the animals were euthanized, and thrombi were harvested and weighed. All organs were cut in thin slices and macroscopically inspected for potential (hemorrhagic) adverse events, and tissue samples were taken. Median thrombus weights were 1.1 g (range, 0.8-1.3 g) in the UK+ group vs 1.6 g (range, 1.3-1.9 g) in the UK group (P = .01). Arterial blood flow increased in four of six pigs in the UK+ group by a mean 61% vs in one of four in the UK group, with 1%. Microcirculation and lower limb arterial pressure levels improved after the start of therapy in the UK+ group, contrary to a trend of decline in the UK group. No signs of bleeding complications were observed in either group. In this experimental pilot study, the addition of contrast-enhanced US accelerated the thrombolytic effect of low-dose intra-arterial thrombolysis in peripheral arterial occlusions. Further clinical studies are warranted.

Endovascular Management in Patients with Acute Basilar Artery Obstruction: Low-Dose Intra-Arterial Urokinase and Mechanical Clot Disruption

Mechanical clot disruption for the treatment of acute basilar artery occlusion (BAO) is known to provide a benefit. We aimed to determine the safety, recanalization rate and time-to-flow restoration of mechanical clot disruption and low dose urokinase (UK) infusions for the treatment of patients with acute BAO. Between June 2006 and June 2010, 21 patients with acute BAO underwent endovascular treatment that included angioplasty or stent placement. The time to treatment, duration of the procedure, dose of urokinase (UK), recanalization rates and symptomatic hemorrhages were analyzed. Clinical outcome measures were assessed at admission and at the time of discharge using the National Institutes of Health Stroke Scale (NIHSS) score and at three months after treatment using the modified Rankin Score (mRS). On admission, the median NIHSS score was 13.2. Median time from symptom onset to arrival at hospital was 356 minutes, and median time from symptom onset to intraarterial thrombolysis (IAT) was 49 minutes. We used the following interventional treatment regimens: Intra-arterial (IA) UK and a minimal mechanical procedure (n=14), IA UK with angioplasty (n=1), IA UK with angioplasty and stent placement (n=3) and IA UK with HyperForm (n=3). The recanalization (thrombolysis in cerebral ischemia grade II or III) rate was 90.5% (19/21). There was symptomatic hemorrhage in one patient (4.8%). The median NIHSS score at discharge was 6.3. The three-month outcome was favorable (mRS: 0-2) for 14 patients (66.7%) and poor (mRS: 3-6) for seven patients (33.3%). The overall mortality at three months was 14.3% (three patients died). Low-dose IAT with mechanical clot disruption is a safe and effective treatment for treatment for acute BAO.

Long-term Outcomes of Low-dose Catheter-directed Thrombolytic Therapy: A 5-year Single-center Experience

To determine immediate and long-term outcomes following catheter-directed intraarterial thrombolysis of occluded native arteries and infrainguinal vein grafts by using low-dose tissue-type plasminogen activator (tPA) in patients with lower limb ischemia. One hundred eleven intraarterial thrombolysis procedures were performed in 96 patients during the 2-year study period. Patient records were available for retrospective review in 85 thrombolytic procedures performed in 74 (77%) of the 96 patients. Forty-one native vessels (four iliac, 24 superficial/common femoral, and 13 popliteal/below-knee vessels), six iliac stents, and 38 infrainguinal vein grafts were treated by using a low-dose (0.5 mg/h recombinant tPA) catheter-directed thrombolytic regimen. Procedural success was based on angiographic and clinical outcomes, and the need for further reconstructive surgery or amputation was documented. Intraarterial thrombolysis was successful in 76%, was partially successful in 11%, and failed in 13%. Adjunctive angioplasty was performed in 33 of 55 patients (60%) with successful lysis, and immediate reconstructive surgery was required in five patients. There was one episode of puncture site bleeding and one gastrointestinal hemorrhage but no procedure-related deaths at 30 days. After a median follow-up of 6.5 years, 30 of the 55 patients (55%) who underwent successful thrombolysis required no further surgical intervention; however, further surgery was required in 45% of patients after a mean interval of 301 days (range, 2-1,344 days), including 10 (18%) amputations (six major and four minor). Low-dose intraarterial thrombolysis is safe and effective, delaying and dramatically reducing the need for surgical intervention in lower limb ischemia due to native vessel or infrainguinal graft occlusion.

Mechanical thrombectomy with snare in patients with acute ischemic stroke

We evaluated the efficacy and safety of thrombus extraction using a microsnare in patients with acute ischemic stroke (AIS). This was a prospective, observational, cohort study in which consecutive patients with AIS (<6 hours of ischemia for anterior circulation and <24 hours for posterior circulation) who had been previously excluded from intravenous tissue plasminogen activator (tPA) thrombolysis were included and followed-up for 3 months. Mechanical embolectomy with a microsnare of 2-4 mm was undertaken as the first treatment. Low-dose intraarterial thrombolysis or angioplasty was used if needed. TIMI grade and modified Rankin stroke scale (mRSS) score were used to evaluate vessel recanalization and clinical efficacy, respectively. Nine patients (mean age 55 years, range 17-69 years) were included. Their basal mean NIHSS score was 16 (range 12-24). In seven out of the nine patients (77.8%) the clot was removed, giving a TIMI grade of 3 in four patients and TIMI grade 2 in three patients. Occlusion sites were: middle cerebral artery (four), basilar artery (two) and anterior cerebral artery plus middle cerebral artery (one). The mean time for recanalization from the start of the procedure was 50 min (range 50-75 min). At 3 months, the mRSS score was 0 in two patients and 3-4 in three patients (two patients died). According to our results, the microsnare is a safe procedure for mechanical thrombectomy with a good recanalization rate. Further studies are required to determine the role of the microsnare in the treatment of AIS.

Low-dose intra-arterial thrombolysis in the treatment of occluded vascular grafts

As the use of intra-arterial thrombolysis increases, its application to specific areas requires definition. The results of treatment of occluded vascular grafts are presented. Thrombolysis using streptokinase or tissue plasminogen activator was planned in the treatment of 18 occluded vascular grafts (five aortofemoral bifurcation grafts and 13 infrainguinal grafts). Two patients, both with infrainguinal occlusions, did not receive thrombolytic therapy and were considered failures of treatment. Successful lysis occurred in three of five aortofemoral grafts, in both infrainguinal vein grafts and in five of nine infrainguinal synthetic grafts. The overall success rate was approximately 60 per cent. Two-thirds of the patients required no intervention following successful lysis. Percutaneous transluminal angioplasty was not found to be a useful additional procedure. A review of the literature revealed that intra-arterial thrombolysis is significantly more successful in the treatment of suprainguinal graft occlusion than in infrainguinal occlusions, there being no difference between infrainguinal vein and synthetic grafts. Provided that the limb is viable and there are no contraindications, intra-arterial thrombolysis is a useful means of clearing occluded grafts.

Differential effects of low-dose tissue plasminogen activator and streptokinase on platelet aggregation

Despite increasing success with low-dose intra-arterial thrombolysis, early rethrombosis still occurs. Platelet aggregation is thought to play a major part in this process. We have therefore investigated the effects of recombinant tissue plasminogen activator (rt-PA) and streptokinase on platelet function at doses currently used for peripheral arterial thrombolysis. Platelet-rich plasma was stirred at 37 degrees C, with either streptokinase (100, 300 or 1000 units ml-1) or rt-PA (10 (T10), 30 (T30) and 100 (T100) mg l-1), with immediate addition of an agonist for platelet aggregation (thrombin, collagen, adenosine diphosphate (ADP) or adrenaline) at a predetermined threshold dose. Significant inhibition of collagen-induced and adrenaline-induced platelet aggregation was produced with rt-PA at all doses used (P less than 0.05). With adrenaline as the agonist, T100 produced disaggregation to a mean (s.d.) level of 26 per cent. Thrombin-stimulated platelet aggregation was significantly reduced by T100 (P less than 0.001) and T30 (P less than 0.01) only, disaggregation being dose-dependent and complete with T100. Using ADP as the agonist, T100 produced a significant reduction in maximum platelet aggregation (P less than 0.01), and disaggregation was achieved to a mean (s.d.) level of 48(13) per cent. Streptokinase did not produce any significant changes in any parameter of aggregation.

Low dose intraarterial thrombolysis with tissue plasminogen activator: does it deliver as promised?

The widespread use of intraarterial thrombolytic therapy has been based on perceived benefits over operative treatment and the downgrading of the magnitude of subsequent surgery. Thirty-three patients who had thrombolysis for peripheral artery occlusion were retrospectively analyzed at St. James's Hospital from 1991 to 1997. One patient received streptokinase unsuccessfully. Five other patient's records were inadequate for analysis. Twenty-seven patient's notes were analyzed for risk, duration of occlusion, duration of treatment, dosage of tissue plasminogen activator (tPA) and conduits thrombolysed. There were 15 males and 12 females. The mean age was 62 years (range, 20-87). Fourteen were current or reformed smokers. Five were diabetic. Indications for treatment included acute graft occlusion (n=13), embolus (n=6), and primary and secondary arterial thrombosis (n=8). Duration of occlusion was less than 24 hours in seven, 1 to 7 days in ten, and more than 7 days in ten patients. Twelve (44.44%) patients had complete clot lysis, four (14.81%) had partial clearance, and 11 (40.74%) remained occluded. Eight (29.63%) had serious complications including one death. Eighteen (66.66%) patients needed further surgical intervention to maintain graft patency. Data were analyzed using the chi-square and pooled t test. No significant difference was observed in results from thrombolysis from different conduits, gender, etiology, or smoking history. Increased duration of tPA administration was associated with an increased risk of failure. Administration of total dosages greater than 60 mg was associated with a higher risk of failure. Diabetics had a poor outcome (p=0.0520). Only 44 % of patients successfully underwent lysis. A primary surgical option may be a more sensible course than lysis, given that the vast majority of patients ended up having surgery anyway.

Accelerated thrombolysis with high dose bolus t-PA extends the role of peripheral thrombolysis but may increase the risks

Low dose intra-arterial thrombolysis is too slow for many patients with severe acute limb ischaemia. Accelerated thrombolysis with high dose bolus t-PA was used in a consecutive series of 43 patients. Complete or clinically useful lysis was achieved in 39 patients, with a median duration of 7 h. Lysis occurred in 46% in under 4 h. Fifty-six per cent of patients required further procedures after lysis. Eleven per cent suffered a major bleed. The limb salvage rate at 30 days was 56%. Amputation was required in 22% and 22% died. Most deaths were due to associated thrombotic conditions: myocardial infarction (5), pulmonary embolism (1) and malignant thrombosis (1). One patient died from pneumonia two weeks after lysis and two died from renal failure within a week of thrombolysis. The high mortality rate was not associated with bleeding but may reflect the high risks involved in treating this group of patients. High dose bolus t-PA infusion appears to predict immediate outcome of thrombolysis as well as reducing infusion times. It may expand the indications for the non-surgical treatment of acute limb ischaemia to include most patients with the condition. Careful case selection is still necessary for optimal results.

Limitations to the widespread usage of low-dose intra-arterial thrombolysis

Despite encouraging results, intra-arterial thrombolysis (IAT) has not been readily accepted by British surgeons. In an attempt to clarify the reasons for this we sent a postal questionnaire to surgeons with a vascular interest, asking them to define their present attitude towards IAT. Subsequently, we re-analysed our own clinical data in the light of the answers received. In all 134 surgeons (58%) replied to the questionnaire; 48 (38%) never used IAT and 56 (45%) used it only occasionally. When stated, the main reasons for this limited use were the doubts about efficacy (45%) and lack of radiological support (47%). From November 1988 to August 1990 we used IAT for 82 occlusions (streptokinase 74, rt-PA8). Lysis was achieved in 82% of cases when treatment was started within 1 week of symptoms starting, and 62% with symptoms of longer duration. Following successful IAT no further treatment was required in 44% of cases, reconstruction was needed in 26% and angioplasty in 23%, one major amputation was performed. Unsuccessful lysis resulted in reconstruction in 40% of cases. Overall, the limb salvage rate was 89%. Major complications occurred in six cases. One patient sustained a fatal CVA and five bled from the catheter insertion site. Two of these patients required an emergency operation and one other, who had an angioplasty immediately following lysis, died. Minor complications included local haematoma formation (16), catheter problems (6), and allergic reactions (2). After insertion of the perfusing catheter, angiograms (median 4, maximum 10) were performed at intervals, with repositioning of the catheter if necessary, until lysis was complete.(ABSTRACT TRUNCATED AT 250 WORDS)

Fibrinolytic Profiles in Local Low-Dose Thrombolysis with Streptokinase and Recombinant Tissue Plasminogen Activator

Fibrinolytic parameters have been monitored in 44 patients undergoing local low-dose intra-arterial thrombolysis for acute peripheral arterial ischaemia. Streptokinase (Sk), at a dose of 5,000 units/hr with 250 units/hr heparin, was used in 23 patients and recombinant tissue plasminogen activator (r-tPA) at a dose of 0.5 mg/hr was used in 21 patients. Successful lysis was seen in 18 (86%) patients following r-tPA and in 15 (65%) patients following streptokinase. There were 4 minor haematomas in each group usually at the catheter entry site. Both agents produced a systemic effect, which was still seen 12 hours post-infusion. However, that produced by r-tPA was delayed and significantly reduced compared to that produced by Sk. These results confirm the relative fibrin specificity of r-tPA. When used as a continuous low-dose intra-arterial infusion, r-tPA offers a significantly lower, potentially safer, systemic effect than conventional therapy with streptokinase.