Catheter-Directed and Pharmacomechanical Thrombolysis for the Treatment of Acute Iliofemoral Deep Venous Thrombosis

Introduction

The majority of physicians treat patients with iliofemoral deep venous thrombosis (DVT) with anticoagulation alone, despite a growing body of evidence that these patients suffer more severe postthrombotic morbidity and higher recurrence rates than patients with infrainguinal DVT. Although there have been enormous advances in anticoagulation therapy (e.g., low-molecular-weight heparins, pentasaccharides, and direct thrombin inhibitors), these agents serve to limit the progression of thrombosis and, with proper duration of therapy, reduce recurrence. However, anticoagulants are not designed to remove existing thrombus from the deep venous system. Acute iliofemoral DVT is associated with significant postthrombotic morbidity.^1–3 Treatment that removes the thrombus from the iliofemoral venous system and restores patency appears to improve the patient’s clinical condition and reduces long-term postthrombotic morbidity.^4–7 Treatment methods have evolved over time from systemic anticoagulation alone to catheter-directed thrombolysis to pharmacomechanical thrombolytic therapy. With each advance in treatment, there appears to be more effective thrombus resolution, reduction of postthrombotic morbidity, and overall improvement in the health of patients following acute DVT. The latest American College of Chest Physicians (ACCP) evidenced-based clinical practice guidelines echo the importance of treatment designed to eliminate the thrombus in patients with extensive acute proximal DVT. Kearon et al⁴ state that “in selected patients with extensive acute proximal DVT (iliofemoral DVT, symptoms for

Understanding Postthrombotic Venous Disease

The pathophysiology of primary versus postthrombotic venous disease is often unappreciated by many physicians. Consequently, the importance of thrombus removal for the prevention of postthrombotic morbidity, especially in patients with iliofemoral DVT, has been undervalued. The pathophysiology of chronic venous disease (CVD) is ambulatory venous hypertension, which is defined as an elevated venous pressure during exercise.⁵ Shull et al measured ambulatory venous pressures in a cohort of patients who had iliofemoral DVT 3–5 years earlier. Using a threshold of ≤ 30 mmHg to quantify normal venous pressure, they reported that the combination of luminal occlusion and popliteal valve incompetence resulted in the highest ambulatory venous pressures (85 ± 14 mmHg). Studies have consistently demonstrated that patients with chronic venous obstruction have the most severe postthrombotic morbidity.^5,6 Although this is generally true for all segments of the venous system, patients who have multisegment venous involvement^17,8 and iliofemoral obstruction suffer the most profound morbidity. Akesson et al² showed that 95% of patients with iliofemoral DVT treated with anticoagulation alone had ambulatory venous hypertension at 5 years, and 90% suffered symptoms of CVD. During this relatively short follow up, 15% of patients had already developed venous ulceration and another 15% had debilitating symptoms of venous claudication. In 39 exercised patients with iliofemoral DVT who were treated with anticoagulation, Delis et al³ found that 40% complained of venous claudication. All but one patient complained of chronic symptoms of heaviness, swelling, pruritus, pain, and itching.

Benefits of Thrombus Removal

It has become increasingly evident that early thrombus resolution (by whatever means) after the onset of acute DVT is associated with improved outcomes. Experimental observations, natural history studies of acute DVT treated with anticoagulation, venous thrombectomy data, and observations following both systemic and catheter-directed thrombolysis confirm that a strategy of thrombus removal reduces postthrombotic morbidity. Experimental observations of acute DVT in canine models demonstrated that thrombolysis preserves endothelial function by preserving ADP-mediated relaxation and valve competence immediately, and at 4 weeks after therapy, compared with placebo. There was less residual thrombus in veins treated with a plasminogen activator, increasing the likelihood that the vein’s structural integrity would be maintained.^9,10 Valve function was frequently preserved in humans with acute DVT who were treated with anticoagulation alone and had spontaneous lysis occur early.

Rationale for Intrathrombus Catheter-directed Thrombolysis

The mechanism that leads to clot dissolution (via thrombolysis) is the activation of fibrin-bound plasminogen to form the active enzyme plasmin, which dissolves clot.20 During thrombosis, circulating GLU-plasminogen is converted to LYS-plasminogen (in thrombus) as a result of binding to fibrin. LYS-plasminogen has more binding sites for plasminogen activators and is more efficiently activated to plasmin than GLU-plasminogen. Therefore, intrathrombus infusion of plasminogen activators should be the most effective method of thrombolysis. Furthermore, intrathrombus delivery naturally protects plasminogen activators from neutralization by circulating plasminogen activator inhibitors (PAI-1) and also protects the resultant active enzyme plasmin from neutralization by circulating antiplasmins. Catheter-directed delivery of plasminogen activators into the thrombus facilitates thrombolysis, which, in turn, increases the likelihood of a successful outcome. Moreover, accelerated lysis reduces the overall dose and duration of plasminogen activator infusion; consequently, it is reasonable to expect that complications also will be reduced.

Results of Intrathrombus Catheter-Directed Thrombolysis

Numerous reports have emerged demonstrating favorable outcomes of catheter-directed thrombolysis for acute DVT; these have been discussed in detail previously.²¹ Three of the larger reports, combined for a total of 422 patients, document approximately an 80% success rate, as measured by greater than 50% lysis of clot.^22–24 Most of these patients had acute DVT as defined in Bjarnason’s paper as Pharmacomechanical Thrombolysis. Preserving venous valve function and luminal patency is the goal of all strategies of thrombus removal for acute DVT. Generally, the preferred method has been catheter-directed thrombolysis, but adding mechanical methods as an adjunct to catheter-directed lytic therapy is quickly setting a new standard for catheter-based treatment of acute DVT.^29–31 However, using percutaneous mechanical thrombectomy alone is less successful than catheter-directed thrombolysis, and there appears to be a higher incidence of embolic complications with mechanical thrombectomy. In a prospective evaluation of pulse-spray pharmacomechanical thrombolysis of clotted hemodialysis grafts,³² it was found that PE (documented by ventilation perfusion scan) occurred in 18% of patients treated with a plasminogen activator pulse-spray solution versus 64% of patients treated with a heparinized saline pulse-spray solution (P = .04). Since clotted hemodialysis grafts are in direct communication with the venous circulation, they can be considered similar to proximal veins with acute DVT treated with mechanical thrombus disruption alone (in terms of embolic potential). Observations would likely be magnified when treating larger venous thromboses. This is an important concept, suggesting that mechanical intervention without protection and without adding plasminogen activators will increase the risk of embolization. This concept was reinforced by Greenberg et al,³³ who, in an experimental model, evaluated mechanical, pharmacomechanical, and pharmacologic thrombolysis. Their findings, consistent with anecdotal clinical observations, as well as the results reported by Kinney et al,³² demonstrated that pulse-spray mechanical thrombectomy alone was associated with the largest number and greatest size of distal emboli. When urokinase was added to the pulse-spray solution, the embolic particles diminished in number and size and the speed of lysis increased while time-to-reperfusion shortened. Catheter-directed thrombolysis alone was associated with the slowest time-to-reperfusion but the fewest distal emboli. In general, mechanical thrombectomy alone is generally inadequate. Hemolytic complications of rheolytic mechanical thrombectomy are common and occasionally can result in anemia and renal dysfunction. One of the more promising pharmacomechanical treatment options for patients with acute iliofemoral DVT is isolated segmental pharmacomechanical thrombolysis (ISPMT), which uses the Trellis Peripheral Infusion System (Bacchus Vascular, Santa Clara, California). The Trellis is a hybrid catheter that isolates the segment of thrombosed vein between two occluding balloons and infuses a small dose of a lytic agent into the target segment. The intervening catheter assumes a spiral configuration which, when activated, spins at approximately 1500 revolutions per minute for 15 to 20 minutes. Following aspiration of the liquefied and fragmented thrombus, the treated vein segment is re-evaluated and re-treated, if necessary. Once the vein is cleared of thrombus, the catheter is repositioned to treat the next thrombosed segments. Phlebographic evaluation of the result is performed before treating additional segments of the thrombosed vein. Martinez et al³⁴ found that ISPMT offered more effective thrombus removal in less time and with a reduced dose of thrombolytic agent when compared with catheter-directed thrombolysis alone. They treated 43 patients: 16 patients were treated with ISPMT + CDT, 6 with ISPMT alone, and 21 with CDT alone. Patients were treated with ISPMT+ CDT if thrombus persisted after ISPMT. Quantitative assessment of thrombus removal was performed after repeat phlebographic imaging. Overall, patients treated with ISPMT had a larger percentage of their thrombus removed. Moreover, treatment time was shorter (23.4 vs 55.4 hours).

Conclusions

Evidence for a strategy of thrombus removal as the preferred treatment approach for patients with acute iliofemoral DVT comes from randomized trials, observational studies, large and small clinical reports, and basic laboratory research. Catheter-directed thrombolysis is effective and has become safer with the use of direct intrathrombus infusion and adjunctive mechanical techniques. As technology continues to advance and as physicians become more comfortable with catheter-based techniques, lytic infusion times will shorten and more patients will become eligible for catheter-based treatment of their acute DVT. Most importantly, patients treated with a strategy of thrombus removal will be spared the otherwise certain morbidity of the postthrombotic syndrome. The ATTRACT trial, which will be a multicenter, randomized, controlled trial comparing pharmacomechanical thrombolysis versus anticoagulation, will be starting shortly. The pharmacomechanical techniques evaluated will be rheolytic and ISPMT. Outcomes include technical success, QOL, Villalta Scale, and Venous Clinical Severity Score. We expect that this trial will likely confirm what has been stated above.

Dr. Comerota discloses that his a consultant to Bacchus Vascular.

Manuscript submitted December 29, 2008, provisional acceptance given February 19, 2009, final version accepted March 17, 2009.

Address for correspondence: Anthony J. Comerota, MD, Director, Jobst Vascular Center, The Toledo Hospital, 2109 Hughes Dr., Suite 400, Toledo, OH 43606. Email: marilyn.gravett@promedica.org.