Use of Thrombolytics in Vascular and Endovascular Surgery

Abstract

Until recently, acute arterial or venous thromboses were routinely managed with surgical intervention. With the development of effective thrombolytic pharmacologic agents and improved modes of delivery of these agents to the target site, surgery is no longer the only option. Greater understanding and knowledge about the finely orchestrated, counterbalanced processes of coagulation and fibrinolysis/thrombolysis have enabled development of agents and strategies for pharmacologic restoration of vascular patency while reducing or eliminating the need for surgery. An evidence-based rationale now exists for the use of thrombolysis in acute limb ischemia, deep venous thrombosis, stroke, and arteriovenous vascular access thromboses. Thrombolytic agents are valuable ancillary agents that allow a less invasive solution to a variety of thrombotic vascular conditions. Strategies that combine thrombolytic agents with endovascular techniques provide precise delivery of these drugs to the target thrombus. A more widespread adoption of this strategy has been limited primarily owing to problems with the currently available pharmacologic agents. The future of thrombolysis therapy is discussed in terms of data obtained from ongoing and recently completed clinical trials. Efforts to develop and study new thrombolytic agents that act directly on the thrombus without activation of intermediary biochemical steps will provide the next major step forward, as well as the rational basis for expansion of currently accepted indications for the treatment of acute arterial and venous thromboses.

Keywords

acute limb ischemia alfimeprase alteplase arteriovenous graft catheter deep vein thrombosis endovascular percutaneous mechanical thrombectomy plasmin reteplase streptokinase stroke surgery tenecteplase thrombolysis thrombolytic thrombosis urokinase

P rior to the introduction of thrombolytics, acute thrombosis of the arterial or venous tree was managed with operative intervention. As the understanding of competing actions of coagulation and fibrinolysis/thrombolysis has evolved, strategies and agents have been developed to pharmacologically restore patency to the vascular tree with the intent of eliminating or minimizing the need for operative intervention. This report focuses on available thrombolytic agents, methods of delivery, and the evidence-based rationale for use of thrombolysis in acute limb ischemia, deep venous thrombosis (DVT), stroke, and arteriovenous vascular access thromboses. Finally, the future of thrombolysis is discussed in terms of investigations of thrombolytics that have recently completed or are currently in clinical trials.

Thrombolytic Agents

The ideal thrombolytic agent would possess the following properties: •
Ease of administration
•
Lytic activity specific for the target thrombus
•
No lytic activity remote from the target thrombus
•
Rapid lysis time
•
Lysis in a predictable dose-response pattern
•
Lysis monitoring with readily available laboratory tests

Unfortunately, currently available thrombolytics have few, if any, of these properties. This has limited the effectiveness of thrombolytics in various clinical settings despite considerable past efforts to document clinical utility.

The initial experimental work concerning treatment of vascular thromboses with thrombolysis occurred in the 1960s. Initial trials used human plasmin intravenous (IV) injections, but the results were poor owing to the rapid inactivation of plasmin by circulating plasminogen inactivators.^1–4 Consequently, thrombolytic agents were redesigned as plasminogen activators, rather than plasmin, to avoid inactivation when systemically administered. Since their introduction, modifications in plasminogen activators have increased patency at the thrombus while minimizing the unwanted systemic lytic effect in an attempt to reduce remote hemorrhagic events.

The first-generation agents were streptokinase and urokinase. Streptokinase worked as a thrombolytic but was limited by antigenicity. Since streptokinase is isolated from the Streptococcus bacteria, previous exposure to streptokinase or the bacteria could cause antibody formation, making administered streptokinase inactive and occasionally resulting in life-threatening allergic reactions.⁴ With the introduction of urokinase, the use of streptokinase decreased significantly. Urokinase became the predominant thrombolytic agent in the 1990s, but in 1999, questions concerning its manufacturing process and potential viral contamination caused the US Food and Drug Administration (FDA) to halt its production. Urokinase was reintroduced in 2002, after the company corrected the production process.⁵

The other major thrombolytic agent currently in use is alteplase. It is a recombinant tissue plasminogen activator (rtPA) without antigenicity. Third-generation agents, reteplase and tenecteplase, are modified tissue plasminogen activators with improved safety and efficacy profiles.^6–8 Despite the various modifications, all of the agents in use are still associated with a low but irreducible incidence of hemorrhagic complications.

Methods of Thrombolytic Delivery

Systemic IV Method

Thrombolytic agents were initially delivered by IV injection. This was a rapid and easy mode of drug administration, requiring only a peripheral IV catheter. With the development of endovascular catheter technology, catheter-directed thrombolysis (CDT) delivering thrombolytics directly into the thrombus became the preferred mode of administration. In certain applications (ie, myocardial infarction, stroke), however, systemic administration is still frequently used and is the preferred mode of delivery.

Catheter-Directed Thrombolysis

CDT provides a more specific and localized lytic effect but with smaller doses of thrombolytic and shorter infusion times. In comparison with systemic administration, CDT is more efficacious and is associated with fewer hemorrhagic events.^9,10 CDT also has the added advantage of facilitating concomitant endovascular interventions to address existing vessel pathology. The ability to directly deliver the lytic agent into the offending thrombus allows for the use of plasmin-like thrombolytic agents that would normally be inactivated if infused systemically. This article includes discussion of these agents currently in clinical trials.

Percutaneous Mechanical Thrombectomy with Thrombolysis

The concept of percutaneous mechanical thrombectomy (PMT) was first described nearly 20 years ago.^11,12 Current PMT devices disrupt thrombus by a number of different mechanisms: (1) hydrodynamic injection and then aspiration of saline to create a local pressure reduction (the Venturi effect) that disrupts thrombus, (2) motorized marsupialization using rotating blades or propellers to provide a recirculation vortex drawing in thrombotic material and macerating it at the same time, and (3) ultrasonography using a high-frequency wire that sonicates and disrupts thrombus.

Often PMT is combined with a lytic agent to facilitate and accelerate thrombolysis. Endovascular catheters placed for PMT are already adjacent to the thrombus and allow for concomitant administration of thrombolytic agents. After initial mechanical disruption of the thrombus, a greater surface area is available for pharmacologic thrombolysis. This accelerates the lytic therapy and lowers the dose of thrombolytic required, thereby minimizing systemic bleeding complications.¹³

Most FDA-approved PMT devices are for use in arteriovenous access graft thrombosis. Use of PMT in other vascular applications is off-label, with the exception of the “mixing” Bacchus Trellis device and the hydrodynamic Angiojet device, which are FDA approved for infrainguinal arterial applications.^14,15

Current Use of Thrombolytic Therapy

Peripheral Arterial Applications

Initial evidence that thrombolysis could effectively treat the acute arterial occlusion in the ischemic extremity and delay or replace surgical intervention came from several nonrandomized case series.^16–18 Preliminary studies proved CDT to be more safe and efficacious than systemic thrombolytic administration.^9,10 Three randomized, prospective clinical trials provided definitive evidence that there was a role for CDT in specific patient populations with lower extremity arterial thromboses.

The first trial published in 1994 by Ouriel and colleagues was the Rochester Trial.²⁰ The Rochester Trial was a single-institution experience in which 114 patients with less than 7 days of limb-threatening ischemia owing to an acute arterial occlusion were randomly assigned to either open surgical therapy or CDT with urokinase. Similar 12-month limb salvage rates of 82% were reported for both groups, but thrombolysis provided an improved 12-month survival compared with surgery (84% CDT vs 58% surgery; p = .01). The improved survival was attributed to fewer perioperative cardiopulmonary complications in the thrombolysis group (16% CDT vs 49% surgery; p = .001).

The Surgery versus Thrombolysis for Ischemia of the Lower Extremity (STILE) trial, also published in 1994, was a larger, more inclusive trial.²¹ It was a randomized, multicenter study that compared open surgical therapy with CDT using either rtPA or urokinase. All patients with nonembolic occlusions who presented with new or progressive limb ischemic symptoms of up to 6 months’ duration were included in the study. The initial target enrollment for this trial was 1,000, but at the first interim analysis (6 months and 393 patients), enrollment was stopped owing to higher adverse primary outcomes in the thrombolysis group (61.7% CDT vs 36.1% surgery; p < .001). There were significantly greater ongoing or recurrent ischemia (54% CDT vs 25.7% surgery; p < .001) and life-threatening hemorrhage (5.6% CDT vs 0.7% surgery; p = .014), and more vascular complications (9.7% CDT vs 3.5% surgery; p = .032) in the thrombolysis group when compared with the surgical group.

Post hoc analyses of the STILE trial suggested that those with acute limb ischemia, defined as less than 14 days of symptoms, had a lower amputation rate at 6 months when treated with CDT compared with surgery (11% CDT vs 30% surgery; p = .02). In contrast, patients with more than 14 days of ischemia who had surgery had improved 6-month amputation rates (3% surgery vs 12% CDT; p = .01).¹⁹ Additional subgroup analyses showed that patients with acute bypass graft occlusions had a decrease in amputations at 1 year with CDT (20%) versus surgery (48%), p = .026,²² whereas for acute native artery occlusions, there was little difference in the amputation rate with CDT (6%) compared with surgery (0%).²³

The third randomized trial was the Thrombolysis Or Peripheral Arterial Surgery (TOPAS) trial, which was a multicenter trial with 544 patients randomly assigned to either CDT with urokinase or open surgical intervention.²⁴ It differed from the STILE and Rochester trials because it included only patients with acute (< 14 days) arterial or bypass graft occlusions. At 12 months, there were similar amputation-free survival rates (65% CDT vs 69.9% surgery) and mortality (20% CDT vs 17% surgery) in the two groups; however, 46% of the patients in the thrombolysis arm were able to avoid an initial operative intervention, with no difference in long-term outcome. This provided the basis for a strategy of initial CDT in patients with acute arterial occlusions, with surgical intervention reserved for nonresponders. The downside of this strategy was an acceptance of an increased rate of major bleeding (12.5% CDT vs 5.5% surgery; p = .005) and the potential delay in limb revascularization if thrombolysis was unsuccessful.²⁵

Recent consensus statements have addressed the arterial applications of thrombolytic therapy. The Working Party on Thrombolysis in the Management of Limb Ischemia, the Seventh American College of Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic Therapy, and the American College of Cardiology (ACC) and the American Heart Association (AHA) in the ACC/AHA Practice Guidelines for the Management of Patients With Peripheral Arterial Disease agreed that CDT is an effective and beneficial therapy and is indicated as an initial therapy for patients with acute limb ischemia (Rutherford categories I and IIa) secondary to arterial thrombosis.^26–29

Despite the evidence and agreement that CDT is an acceptable option for acute arterial occlusions, one major limitation remains: the time necessary for effective lysis is unpredictable and can range from 4 to 48 hours.^30–32 Current recommendations thus limit the use of CDT to Rutherford category I or IIa limb ischemia, where time to revascularization is not a limiting concern. When time is a concern (ie, Rutherford IIb), operative intervention remains the first-line therapy. In an effort to extend thrombolysis to this timesensitive group, the strategy of thrombolysis with PMT has been used to try to accelerate thrombus clearance.

No randomized studies have compared PMT with operative intervention, but a number of case series do exist. Based on the findings of these studies, recommendations from the 2005 ACC/AHA Practice Guidelines for the Management of Patients With Peripheral Arterial Disease support a selected use of catheter-based thrombolysis or thrombectomy for patients with acute limb ischemia (Rutherford category IIb).²⁷

Even though many centers advocate PMT with lysis as first-line therapy, it is not considered the “standard of care” for acute arterial thrombosis with Rutherford IIb class ischemia.³³ At the present time, the approach is to use PMT as an ancillary to CDT, with the exception of cases in which thrombolysis is contraindicated.¹³ In that setting, physicians must consider the relative merits of PMT alone versus operative intervention on a case-by-case basis.

Venous Applications

Large randomized trials do not exist to guide thrombolytic therapy in the venous system. Currently, most of the advocated approaches with thrombolysis in the management of acute DVT are predicated on nonrandomized clinical series and venous registries.

Initial attempts to treat DVT with thrombolysis involved a number of small clinical trials that compared systemic IV thrombolysis with systemic anticoagulation.^34–37 A meta-analysis of 13 studies encompassing 591 patients with acute DVT found that those patients treated with systemic thrombolysis had improved outcomes compared with patients treated with heparin anticoagulation alone. Complete lysis occurred in 4% versus 45%, partial lysis in 14% versus 18%, and failure to improve in 82% versus 37% of patients in the anticoagulation versus thrombolysis groups, respectively.³⁴ Although thrombolysis clearly provided improved venous patency, data on outcome regarding postthrombotic syndrome were lacking. In addition, the failure rate of systemic lytic therapy in patients with ileofemoral venous thrombosis was high. In an attempt to improve thrombolysis results, Semba and Dake were the first to incorporate CDT into the treatment paradigm.³⁸

In 1999, the results published from a venous registry included 63 institutions that examined outcomes of CDT therapy in 287 patients with DVT. The frequency of substantial lysis (more than 50% of the venous lesion) was 83%, which included a complete lysis (100% of the lesion) rate of 33%. If patients achieved complete lysis, it was more likely to be those with acute (34%) versus chronic (19%) DVT, regardless of the DVT location (ileofemoral or femoral popliteal). The complete lysis group also had an improved 1-year patency of 75% when compared with partial lysis at 32%. Major bleeding complications occurred in 11% of the patients, most often at the puncture site. One percent of patients developed pulmonary emboli, and two deaths were attributed to pulmonary embolism and intracranial hemorrhage.³⁹

To date, data are available for only a small randomized trial of CDT versus anticoagulation. In 2002, Elsharawy and Elzayat examined 35 patients with acute ileofemoral DVT and randomly assigned them to CDT or anticoagulation alone.⁴⁰ At 6 months, patency rates were better in cases treated with CDT versus anticoagulation (72% vs 12%; p < .0001), and less venous reflux (11% CDT vs 41% surgery; p = .04) was documented.

Recommendations from the ACCP Conference on Antithrombotic and Thrombolytic Therapy discourage the use of either systemic thrombolytic or CDT for acute DVT. It was acknowledged that systemic thrombolysis and CDT resulted in improved venous patency, but the higher risk of bleeding with thrombolysis negated this benefit. The conference did recommend thrombolytics as first-line therapy in one specific clinical setting, namely, “in selected patients such as those with massive ileofemoral DVT at risk of limb gangrene secondary to venous occlusion.”²⁶

One advantage of CDT over anticoagulation alone is that it can identify and correct the anatomic etiology of thrombosis. Initial thrombolysis followed by angioplasty and stenting of the left iliac vein stenosis has treated patients with May-Thurner syndrome complicated by DVT successfully in a number of case series.^41,42 In the previously mentioned venous registry, in addition to CDT, concomitant angioplasty and stenting were used in 33% of the cases³⁹ and have been used as often as 67% in other case series.⁴³

The use of PMT coupled with CDT also has been employed for acute DVT. In 2006, a parallel, nonran-doamized case series compared 46 patients who received CDT alone with 52 patients who received PMT by Angiojet catheter followed by thrombolysis for the treatment of DVT. The results between the CDT and PMT-CDT groups were similar in terms of complete thrombus removal (70% CDT vs 75% PMT-CDT), partial thrombus removal (30% CDT vs 25% PMT-CDT), need for venous angioplasty or stenting (78% CDT vs 82% PMT-CDT), and 1-year patency (64% CDT vs 68% PMT-CDT). There were significant reductions, however, in the intensive care stay (0.6 days CDT vs 2.4 days PMT-CDT; p < .04) and hospital lengths of stay (4.6 days CDT vs 8.4 days PMT-CDT; p < .02). Hospital costs were also lower in the PMT group ($85,301 CDT vs $47,742 PMT-CDT; p < .01).⁴²

Currently, systemic thrombolysis, CDT, and PMT alone or in combination are not standard therapy for acute DVT, even in the ileofemoral system. This will change if a randomized trial demonstrates that thrombolysis, when compared with anticoagulation, provides improved long-term results for postthrombotic syndrome, with similar bleeding complication rates.

Cerebral Vasculature Applications

The use of thrombolysis in acute stroke has become standard therapy after a series of well-controlled randomized trials. Currently, there is level 1 evidence for IV thrombolysis and intra-arterial (IA) CDT for acute stroke.

Four well-controlled, randomized clinical trials established the criteria for IV thrombolytic use in stroke. The National Institute of Neurological Disorders and Stroke (NINDS) was the first to show that IV rtPA provided a superior neurologic outcome at 3 months when compared with placebo if used within a 3-hour window of stroke onset.³ The European Cooperative Acute Stroke Study (ECASS) extended the window to 6 hours, but the trial results were inconclusive because of a large number of protocol violations.⁴⁴ In ECASS II, there was no difference in neurologic outcome between systemic rtPA and placebo.⁴⁵ The Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) trial studied patients presenting in the 3-to 5-hour window and found no significant differences in any of the secondary functional outcome measures but noted an increase in intracranial hemorrhage in the rtPA groups.⁴⁶

Based on this evidence, the ACCP Conference on Antithrombotic and Thrombolytic Therapy recommended IV rtPA for acute ischemic stroke within 3 hours of symptom onset in a dose of 0.9 mg/kg (maximum of 90 mg), with 10% of the total dose administered as an initial bolus and the remainder infused over 60 minutes. For patients with acute stroke of > 3 hours but < 6 hours, IV rtPA was not recommended.⁴⁷

IA CDT for acute stroke has been studied as well. One pivotal trial was the Prolyse in Acute Cerebral Thromboembolism II (PROACT II) study.⁴⁸ Patients were randomly assigned to either IA CDT with urokinase followed by IV heparin versus IV heparin alone. Patients included were those who presented within 6 hours of stroke onset with angiographically documented proximal middle cerebral artery occlusion. In the urokinase arm, there were higher rates of partial (66% urokinase vs 18% heparin) and complete recanalization (19% urokinase vs 2% heparin). Neurologic outcome was numerically improved in the urokinase arm, but the numbers were too small for statistical analysis. There was no difference in mortality, but the rates of intracranial hemorrhage at 24 hours were higher for the urokinase group (10% urokinase vs 2% heparin).^48,49

Three recent nonrandomized trials have combined IV and IA thrombolysis: the Interventional Management of Stroke (IMS),⁵⁰ the IMS II,⁵¹ and the Emergency Management of Stroke (EMS).⁵² With IA and IV thrombolysis, IV thrombolysis is administered initially to avoid treatment delays while the interventional team prepares to later administer IA CDT directly to the thrombus.

The IMS (N = 80) and IMS II (N = 81) were single-arm studies involving patients with less than 3 hours of symptoms. The IMS II included the use of the EKOS ultrasound PMT device. Both studies found less mortality (16% for both) than the historical data from the NINDS rtPA (24%) and placebo (21%) groups. Symptomatic intracranial hemorrhage rates were similar across the board, with better 3-month neurologic outcomes for the IMS II patients when compared with historical data and IMS.^3,50,51

The EMS study used IA CDT thrombolysis alone. Thirty-five patients with 3 hours of symptoms were randomly assigned to placebo or IA thrombolysis or IV or IA thrombolysis. Better recanalization was evident in the IV-IA group, but no difference in neurologic outcomes or intracranial hemorrhage between the groups was demonstrated.⁵²

A number of well-performed studies provide good evidence for the use of thrombolytics in the management of acute stroke. Ongoing studies continue to refine the current treatment strategies with thrombolysis.

Arteriovenous Graft Applications

For the management of arteriovenous graft (AVG) occlusion, there are three options for use in combination or individually: operative thrombectomy, CDT, and PMT. A 2002 meta-analysis reported on all randomized trials of AVG thrombosis comparing operative thrombectomy with any endovascular therapy. Operative therapy was found to be superior in every aspect when compared with the endovascular approaches. There were no standardized reporting guidelines, however, and endovascular therapy included a wide range of techniques, from CDT to early mechanical thrombectomy techniques that are no longer used today.⁵³

When comparing CDT and PMT, two randomized studies have demonstrated the Arrow-Trerotola rotational PMT and Oasis hydrodynamic PMT devices to have similar patency rates compared with CDT but with shorter treatment times.^54,55

At the present time, strong data supporting any one treatment for AVG thrombosis do not exist, and the competing application of operative thrombectomy, CDT, and PMT should be individualized based on the clinical setting and physician preference.

New Thrombolytic Agents

Currently available thrombolytic agents are all plasminogen activators and thus work by converting inactive plasminogen to active plasmin, which then acts on the thrombus to cleave linked fibrin. Since the effect of plasminogen activators is indirect, the thrombolytic effect is dependent on a sufficient supply of plasminogen within the target thrombus for full and complete lysis. Plasminogen activators are also inactivated by endothelial cell– and platelet-derived plasminogen activator inhibitor 1. These aspects of plasminogen activators as therapeutic thrombolytic agents contribute to the need for extended infusion times, the resistance of platelet-rich arterial thromboses to thrombolysis, and the troubling occurrence of major bleeding and intracerebral hemorrhage.⁵⁶ The refinement of endovascular technology allowing for direct thrombolytic delivery to the thrombus has regenerated interest in the development of “plasmin”-type agents that can act directly on the thrombus.

Alfimeprase

Alfimeprase is a recombinant zinc metalloproteinase that was first isolated from the venom of the southern cop-perhead snake. It is a fibrinolytic and acts directly on the fibrinogen Aa chain. Preclinical studies suggested that thrombolysis occurred up to six times faster with alfimeprase compared with plasminogen activators.⁵⁷

Alfimeprase has been investigated in two distinct clinical settings: catheter occlusion and acute arterial occlusion. Catheter occlusion was studied by the Speedy Opening of Nonfunctional and Occluded Catheters With Minidose Alfimeprase (SONOMA) trial. Phase II studies demonstrated that alfimeprase was safe and more effective than alteplase at opening occluded catheters at all doses tested.⁵⁸ In a more recently completed pivotal trial, SONOMA 2, the primary end point of superior catheter opening with alfimeprase when compared with alteplase at 15 minutes was not achieved.

The Novel Arterial Perfusion with Alfimeprase (NAPA) 1 trial was a phase II dose-escalation study of the safety of alfimeprase to treat acute peripheral arterial occlusions. Major bleeding complications were uncommon at all doses, and > 50% of patients avoided open surgical intervention; however, these positive findings were tempered by a 20% incidence of hypotension at the highest dose.⁵⁹ Although the phase II trial results were promising, the pivotal phase III trial (NAPA 2) that compared alfimeprase with placebo did not meet its primary end point. There was a failure to achieve a significant reduction in the need for open vascular surgery within 30 days of treatment in the alfimeprase arm when compared with placebo.^60,61

The future of alfimeprase in clinical applications remains unclear. The manufacturer Nuvelo has relaunched its catheter occlusion study and plans on proceeding with a new study of alfimeprase in acute stroke.⁶² The method of delivery and dosing schedules of arterial occlusion applications are undergoing further investigation in animal studies in an effort to optimize the thrombolytic activity of alfimeprase.

Plasmin

Another new agent under investigation is human plasmin. As with alfimeprase, it acts directly on the fibrin clot and does not need activation. As discussed earlier, plasmin has been used in the past, but the results were poor when given systemically, mainly because of rapid inactivation from plasma α₂-antiplasmin.⁶³ With catheter-directed therapies, it is hypothesized that plasmin will outperform the current thrombolytic agents, as already demonstrated in animal studies.⁶⁴ The risk of systemic bleeding would also theoretically be less given the rapid systemic inactivation. Active enrollment in phase I and II clinical trials is ongoing with the Plasmin Revascularization by Intrathrombus Infusion for the Ischemic Lower Extremity (PRIORITY) study.

Summary

Thrombolytics are valuable ancillary agents that allow a less invasive solution to various thrombotic vascular conditions. The incorporation of endovascular techniques to everyday vascular practice provides the platform for precise delivery of thrombolytics to the target thrombus. The main limitation to a more widespread use of this strategy is the less-than-optimal characteristics of currently available thrombolytics. Efforts to develop and study new thrombolytics that act directly on the thrombus without intermediary biochemical steps will provide the next major advance in the use of thrombolytics and serve to expand currently accepted indications for the treatment of acute arterial and venous thromboses.

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